Hafez A. Ahmed

Prescribing habits in primary biliary cirrhosis : a national survey

BACKGROUND Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown aetiology. A number of drugs have been used in its treatment, but only ursodeoxycholic acid (UDCA) has been shown to improve survival. Our aims were to determine the current prescribing habits in PBC of all practising gastroenterologists in the UK. METHODS A postal questionnaire was sent to 454 gastroenterologists in 1996, followed by a second questionnaire a month later to the non-responders. RESULTS Of 454 doctors sent questionnaires, 379 (83%) replied. Of these, 58 were excluded from further analysis as they were not practising gastroenterologists. There are an estimated 4337 patients with PBC being seen by gastroenterologists in hospitals. Of these, only 1376 (32%) are being seen in liver units. Ninety-one per cent of gastroenterologists look after patients with PBC (median 10 patients, range 1-500). Ninety-five per cent of gastroenterologists prescribe UDCA but there is a large dose range (median 11.5 mg/kg/day, range 1.5-23.1). Of these, 93% also prescribe cholestyramine. Only 45 (14%) gastroenterologists prescribed other treatments for PBC (13 colchicine, 24 steroids, nine penicillamine, 13 immunosuppressants). Only 53 (17%) treat the symptoms/complications of PBC (37 fat-soluble vitamins, 15 calcium, six bisphosphonates, one hormone replacement therapy, 10 antihistamines, 10 rifampicin). CONCLUSIONS UDCA is being prescribed for PBC by the majority of practising gastroenterologists but over a wide dose range. Very few gastroenterologists are using preventive treatment for osteoporosis in this high-risk group. Other treatments, as yet unproven in trials, are being prescribed by a minority of gastroenterologists.

A critical review of the Couvade syndrome: the pregnant male

The Couvade syndrome is a global phenomenon occurring in industrialised countries around the world and has a wide international variance. It affects biological fathers particularly during the first and third trimesters of pregnancy with cessation of symptoms upon birth or shortly within the postpartum period. It does not appear in the nosology of the Diagnostic Statistical Manual of Mental Disorders: DSM—Version 4 (American Psychiatric Association, 2000) on the ICD—Version 10 (WHO, 1993). Nevertheless, early accounts tended to medicalise it as a psychosomatic disorder. Its relationship with socio‐demographic factors is inconsistent, with the exception of ethnicity. International studies reveal some contradictory findings in the type of symptoms. This may reflect methodological problems in the syndromes definition or criteria and type of measurement across studies. A plethora of theories has been put forward to account for the origins of the syndrome. Psychoanalytical theories contend that it is a consequence of the mans envy of the womans procreative ability or foetal rivalry. Psychosocial theories propose that it occurs due to the marginalisation of fatherhood and as part of a transitional crisis to parenthood. Paternal theories suggest a connection between the mans involvement in pregnancy, role preparation and the syndrome. However, some of these theories have not been thoroughly investigated. Those which have reveal inconsistent findings. It is recommended that future investigators use qualitative approaches to further illuminate the syndromes characteristics, definition and perceptions as seen by male partners. This should be followed by quantitative approaches of large heterogeneous samples to investigate the type, incidence, severity and distress of symptoms of the syndrome and its relationship with socio‐demographic factors.

Increased serum gamma-glutamyl-transpeptidase concentration is associated with nonalcoholic steatosis and not with cholestasis in patients with chronic hepatitis C

Background and Aim:  Increased pretreatment gamma‐glutamyl‐transpeptidase (γGT) is common in patients with chronic hepatitis C and with little or no alcohol consumption. The mechanism involved in this phenomenon is unclear, and the aim of this study was to investigate factors associated with increased γGT levels, specifically looking at the role of cholestasis that frequently accompanies hepatitis C.

A qualitative exploration of the Couvade syndrome in expectant fathers

The aim of this qualitative study is to explore the nature and duration of male partners somatic and psychological symptoms, across gestation and parturition, collectively called the Couvade syndrome. Fourteen men with expectant partners aged 19–48 years from diverse social and ethnic backgrounds were interviewed. The data was processed using qualitative analytical software WinMAX Professional and the emerging themes and sub‐categories identified and analysed. The first was ‘Emotional Diversity in Response to Pregnancy’, which varied with time and other factors and also included mixed and polarised feelings such as excitement, pride, elation, worries, fears, shock and reluctance. The second was ‘Nature, Management and Duration of Symptoms’, which revealed the types and duration of physical and psychological symptoms experienced by men. Attempts at managing these were influenced by social and cultural factors. Physical symptoms were more common than psychological ones, and their time course demonstrated trends similar to those reported for the Couvade syndrome. Although the former were reported to their GPs, no definitive diagnosis was made despite medical investigations being performed. The third theme, ‘Explanatory Attempts for Symptoms’ was influenced by cultural beliefs and conventions like religion, alternative medical beliefs or through the enlightenment by healthcare professionals in the process. Some participants were unable to find explanations for symptoms but some perceived that they were related in some way to the altered physiology of their female partners during pregnancy. These findings highlight the need for further research to acquire deeper insight into mens experiences of, and responses to, pregnancy as a way of explaining the syndrome.

Demonstration and partial characterisation of phospholipid methyltransferase activity in bile canalicular membrane from hamster liver.

Abstract Background/Aims: Methylation of phosphatidylethanolamineto phosphatidylcholine predominantly takes place in mitochondrial-associated membrane and the endoplasmic reticulum of the liver. The transport of the phospholipids from endoplasmic reticulum to the bile canalicular membrane is via vesicular and protein transporters. In the bile canalicular membrane a flippase enzyme helps to transport phosphatidylcholine specifically to the biliary leaflet. The phosphatidylcholine then enters the bile where it accounts for about 95% of the phospholipids. We postulated that the increased proportion of phosphatidylcholine in the bile canalicular membrane and the bile compared to the transport vesicles may be due to a methyltransferase activity in the bile canalicular membrane which, using s-adenosyl methionine as the substrate, converts phosphatidylethanolamine on the cytoplasmic leaflet to phosphatidylcholine, which is transported to the biliary leaflet. The aim of our study was to demonstrate and partially characterise methyltransferase activity in the bile canalicular membrane. Methods: Organelles were obtained from hamster liver by homogenisation and separation by sucrose gradient ultracentrifugation. These, along with phosphatidylethanolamine, were incubated with radiolabelled s-adenosyl methionine. Phospholipids were separated by thin-layer chromatography and radioactivity was counted by scintigraphy. Results: We demonstrated methyltransferase activity (nmol of SAMe converted/mg of protein/h at 37°C) in the bile canalicular membrane of 0.442 (SEM 0.077, n =8), which is more than twice that found in the microsomes at 0.195 (SEM 0.013, n =8). The Km and pH optimum for the methyltransferase in the bile canalicular membrane and the microsomes were similar (Km 25 and 28 μM, respectively, pH 9.9 for both). The Vmax was different at 0.358 and 0.168 nmol of SAMe converted/mg of protein/h for the bile canalicular membrane and the microsomes, respectively. Conclusion: The presence of the methyltransferase activity in the bile canalicular membrane may be amenable to therapeutic manipulation.

Effects of bile acids on human hepatic mitochondria

Objectives: The mechanisms underlying hepatic damage in cholestasis and the beneficial effect of ursodeoxycholic acid (UDCA) are unclear. It has been hypothesized that hydrophobic bile acids retained in the hepatocytes damage mitochondria, but that UDCA is less damaging and even directly protective. We examined the effect of taurine conjugates of UDCA and other bile acids on the electron transport chain of human hepatic mitochondria to determine whether tauro-UDCA can modulate the potentially toxic effects of more hydrophobic bile acids. Methods: Wedge liver biopsies (n = 6) were obtained from individuals without liver disease. Mitochondria, microsomes and cytosol were isolated by differential and sucrose gradient ultracentrifugation and incubated with taurine conjugates of UDCA, cholic, chenodeoxycholic and deoxycholic acids in concentrations ranging from 500 to 5000mmol/l. Mitochondrial succinate cytochrome C reductase, microsomal NADPH cytochrome C reductase, cytosolic glucose 6-phosphate dehydrogenase and bile acid induced protein solubilization from mitochondria were measured. Results: The inhibition of succinate cytochrome C reductase activity was first detected with tauro-deoxycholic acid at 1 mmol/l, with tauro-chenodeoxycholic acid at 1.5 mmol/l, but not with tauro-UDCA, even at 5 mmol/l. Neither NADPH cytochrome C reductase nor glucose 6-phosphate dehydrogenase were inhibited by any of the bile acids up to the highest concentration studied. Tauro-chenodeoxycholic acid solubilized significantly more protein than UDCA. The addition of 2 mmol/l tauro-UDCA protected mitochondrial function, but the effect on mitochondrial membrane structure was less clear. Conclusion: Hydrophobic bile acids are particularly damaging to human hepatocyte mitochondria; they can solubilize protein and inhibit succinate cytochrome C reductase activity. Tauro-UDCA is not only less damaging but can reduce the damaging effects of more hydrophobic bile acids.

Demonstration and partial characterisation of phospholipid methyltransferase activity in bile canalicular membrane from hamster liver

BACKGROUND/AIMS Methylation of phosphatidylethanolamine to phosphatidylcholine predominantly takes place in mitochondrial-associated membrane and the endoplasmic reticulum of the liver. The transport of the phospholipids from endoplasmic reticulum to the bile canalicular membrane is via vesicular and protein transporters. In the bile canalicular membrane a flippase enzyme helps to transport phosphatidylcholine specifically to the biliary leaflet. The phosphatidylcholine then enters the bile where it accounts for about 95% of the phospholipids. We postulated that the increased proportion of phosphatidylcholine in the bile canalicular membrane and the bile compared to the transport vesicles may be due to a methyltransferase activity in the bile canalicular membrane which, using s-adenosyl methionine as the substrate, converts phosphatidylethanolamine on the cytoplasmic leaflet to phosphatidylcholine, which is transported to the biliary leaflet. The aim of our study was to demonstrate and partially characterise methyltransferase activity in the bile canalicular membrane. METHODS Organelles were obtained from hamster liver by homogenisation and separation by sucrose gradient ultracentrifugation. These, along with phosphatidylethanolamine, were incubated with radiolabelled s-adenosyl methionine. Phospholipids were separated by thin-layer chromatography and radioactivity was counted by scintigraphy. RESULTS We demonstrated methyltransferase activity (nmol of SAMe converted/mg of protein/h at 37 degrees C) in the bile canalicular membrane of 0.442 (SEM 0.077, n=8), which is more than twice that found in the microsomes at 0.195 (SEM 0.013, n=8). The Km and pH optimum for the methyltransferase in the bile canalicular membrane and the microsomes were similar (Km 25 and 28 microM, respectively, pH 9.9 for both). The Vmax was different at 0.358 and 0.168 nmol of SAMe converted/mg of protein/h for the bile canalicular membrane and the microsomes, respectively. CONCLUSION The presence of the methyltransferase activity in the bile canalicular membrane may be amenable to therapeutic manipulation.