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SummaryBackground The systemic immune system plays a role in inflammation and fibrogenesis associated with non-alcoholic steatohepatitis (NASH) and has become a potential target for drug development. In particular, the gut immune system has been suggested as a means for generating signals that can target the systemic immune system. Aim To describe seven novel methods being developed for the treatment of NASH that target the gut immune system for alleviation of the systemic inflammatory response, including oral administration of fatty-liver-derived proteins, anti-CD3 antibodies, tumour necrosis factor fusion protein, anti-lipopolysaccharide antibodies, glucosylceramide, delayed-release mercaptopurine, and soy-derived extracts. Methods A search for these methods for oral immunotherapy for NASH was conducted. Results Oral administration of these compounds provides an opportunity for immune modulation without immune suppression, with the advantage of being independent of a single molecular/inflammatory pathway. These modes of oral immune therapy demonstrate superior safety profiles, such that the patient is not exposed to general immune suppression. Moreover, these approaches target the whole spectrum of the disease and may serve as adjuvants to other therapies, such that they provide a platform for treatment of concomitant disorders in patients with NASH, including diabetes and hyperlipidaemia. Most of the compounds reviewed are currently in phase II trials, and it is anticipated that the acquisition of more clinical data in the next few years will enable the use of this new class of drugs for the treatment of NASH. Conclusion Oral immunotherapy may provide a novel platform for the treatment of NASH.

Correction of enzyme activity was successfully accomplished in β-glucuronidase deficient C3H/HeJ mice after intrasplenic transplantation of isolated hepatocytes obtained from normal Balb/C donors mice. Enzyme activity increased from a mean of 1.1 ± 0.2 nmol/h/ml on day 0 to 15.8 ± 3.3 nmol/h/ml on day 55 post-transplantation. Examination of enzyme activity in liver tissue by repeated liver biopsies revealed an increase in β-glucuronidase activity from a mean of 1.85 ± 0.6 nmol/h/mg protein on day 0 up to 42.6 ± 7.3 nmol/h/mg protein on day 35 post-transplantation. β-Galactosidase and β- N -acetyl-glucosaminidase activities were not significantly changed throughout the study. Intrasplenic transplantation of hepatocytes isolated from β-glucuronidase-deficient mice did not induce a significant change in three examined hydrolases. These results suggest that transplantation of isolated hepatocytes may be used as an effective tool for therapy of lysosomal enzyme deficiency in mice.

Giant cell arteritis is a vasculitis which usually affects large and medium-sized vessels in patients over 50 years old. The liver is one of the internal organs which can be involved in this systemic disease. During the last 15 years, 56 patients with giant cell arteritis were seen in our hospital. In 12 patients disturbed liver function tests were found. In the majority of cases the disturbance was of cholestatic type and resolved completely with steroid treatment. The association of temporal arteritis with disturbed liver function tests is discussed, with a review of the recent literature.

Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver failure. In view of the effects of cannabinoids in a thioacetamide-induced model of hepatic encephalopathy and liver disease and the beneficial effect of capsaicin (a TRPV1 agonist) in liver disease, we assumed that capsaicin may also affect hepatic encephalopathy.Fulminant hepatic failure was induced in mice by thioacetamide and 24 h later, the animals were injected with one of the following compound(s): 2-arachidonoylglycerol (CB(1), CB(2) and TRPV1 receptor agonist); HU308 (CB(2) receptor agonist), SR141716A (CB(1) receptor antagonist); SR141716A+2-arachidonoylglycerol; SR144528 (CB(2) receptor antagonist); capsaicin; and capsazepine (TRPV1 receptor agonist and antagonist respectively). Their neurological effects were evaluated on the basis of activity in the open field, cognitive function in an eight-arm maze and a neurological severity score. The mice were killed 3 or 14 days after thioacetamide administration. 2-arachidonoylglycerol and 5-hydroxytryptamine (5-HT) levels were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography with electrochemical detection, respectively.Capsaicin had a neuroprotective effect in this animal model as shown by the neurological score, activity and cognitive function. The effect of capsaicin was blocked by capsazepine. Thioacetamide induced astrogliosis in the hippocampus and the cerebellum and raised brain 5-hydroxytryptamine levels, which were decreased by capsaicin, SR141716A and HU-308. Thioacetamide lowered brain 2-arachidonoylglycerol levels, an effect reversed by capsaicin.Capsaicin improved both liver and brain dysfunction caused by thioacetamide, suggesting that both the endocannabinoid and the vanilloid systems play important roles in hepatic encephalopathy. Modulation of these systems may have therapeutic value.

One hundred and 15 hospitalized patients with acute pericarditis were analyzed retrospectively for their etiology, management and long-term prognosis. It was found that most of the patients had either idiopathic or viral etiologies (60%), collagen disease (16.4%) or malignancy (6.9%). Most of the patients were treated with non-steroidal anti-inflammatory drugs (NSAID). Twenty-six patients (22%) required corticosteroids following NSAID treatment failure. Only one patient underwent pericardiocentesis for tuberculous pericarditis. The long-term prognosis was good, although 21.9% of the patients suffered from recurrent episodes of pericarditis. It is concluded that in hospitalized patients with pericarditis, an extensive workup may not reveal the major etiologies, and the disease may be more complicated than previously thought.

A new method for producing polymeric permeable membranes isdescribed. It is based on inducing chemical decomposition in molecularly dispersed molecules compatible with the polymer which forms the membrane. Decomposition products, which are small molecules, either leave the polymeric matrix, forming pores, or are trapped, and thus may provide for affecting transport through chemical interactions. In this first article the concept is described and illustrated by using polysulfone (PS) as the polymer and di- N -boc-diaminohexane [(CH 3 3 C O C:O NH (CH 2 ) 6 NH C:O O C(CH 3 ) 3 , DBDAH] as the porogen. Possible effects of various parameters are analysed.

Summary Background Hepatologists have long sought to develop a test for assessing liver function, but this aim has been stalled by the complexity of the liver and its diverse functions. Results of metabolic tests, including breath tests, correlate with clinical and histological parameters of patients with liver disorders; however, these tests tend to be cumbersome and impractical for everyday use. The recent development of a real-time, point-of-care liver function breath test has made it straightforward to assess the metabolic function of the liver. Aim To review the available data on the use of breath tests for assessing liver reserve in various conditions and their application in various clinical hepatology settings. Results The 13C-methacetin breath test enables accurate follow-up of patients with acute or chronic liver damage, where overall hepatic function is significantly suppressed by known causes of liver disorders, including acute, sub-acute or chronic conditions. The metabolic breath test can detect both gradual and spontaneous improvements in liver function and the effects of treatment. Conclusions Breath testing that provides continuous quantification of methacetin metabolism may be a sensitive tool for the diagnosis and follow-up of patients with liver disorders.

Budd-Chiari Syndrome (BCS) refers to hepatic venous outflow obstruction, resulting in simultaneous occurrence of hepatic congestion and portal hypertension, leading to a typical clinical triad consisting of right upper quadrant pain, hepatomegaly and ascites. Contrary to Asia and Africa, where BCS is caused primarily by an obstructing membranous web, BCS in the western world is considered a thrombotic complication of an underlying hypercoagulable state. Recognition of the contribution of hypercoagulability as a causative factor in BCS, has led to acknowledgement of the importance of anti-coagulant therapy in BCS. Indeed, a conservative approach consisting of diuretics and anti-coagulant therapy is considered an appropriate treatment strategy for the BCS patient, in the absence of significant hepatic insult. However, once disease progression is noted, based on clinical symptoms, hepatic laboratory disturbance or histological evidence of irreversible hepatic damage, a definite invasive treatment should be applied. The specific procedure to be used is dependent upon the extent of hepatic insult and the anatomical characteristics of the venous obstruction in any individual patient. In the absence of significant hepatic damage, one may employ surgical shunting or invasive roentgenic measures, such as TransJugular Intrahepatic Porto-Systemic Shunt procedure, for the decompression of the portal system. Alternatively, in cases of a single localized obstruction, one may use balloon angioplasty with stent insertion. In contrast, upon evidence of significant hepatic damage, liver transplantation becomes necessary. To date, numerous studies report excellent results regarding the success of liver transplantation for patients with advanced BCS disease accompanied by significant hepatic damage.

Primary sclerosing cholangitis (PSC), a condition usually associated with inflammatory bowel disease, is a chronic inflammatory state of the biliary tract characterized by fibrotic strictures of intrahepatic and extrahepatic bile ducts. Between 5-15% of patients with PSC will develop cholangiocarcinoma. The diagnosis of cholangiocarcinoma in patients with PSC is difficult, as it is often impossible to distinguish benign PSC-related strictures from lesions associated with cholangiocarcinoma. Consequently, most patients are diagnosed with advanced disease and have a dismal prognosis at the time of diagnosis. The importance of characterizing patients with PSC who have an increased risk of developing cholangiocarcinoma and of developing means for early detection of this disease cannot be over-emphasized. Detection of cholangiocarcinoma in asymptomatic patients is additionally important, as this condition is considered a contraindication for liver transplantation. We describe a patient with longstanding Crohn's disease and PSC who developed cholangiocarcinoma, and review the literature regarding risk factors for cholangiocarcinoma, early detection of cholangiocarcinoma and the significance of existing cholangiocarcinoma in the context of liver transplantation.

HUMAN cytomegalovirus (CMV) is a major pathogen in patients undergoing orthotopic liver transplantation (OLT). Infection is common, with an incidence of 23% to 85%; symptomatic disease develops in 15% to 40%. Clinical manifestations range from persistent fever with mononucleosis-like syndrome to severe visceral disease involving the lung, liver, and other organs such as the eye or brain. In addition to its direct effect, CMV has been associated with increased risk for bacterial and fungal infection, and with allograft dysfunction. Several risk factors for CMV disease have been recognized, including the serologic status of the donor and recipient, treatment with OKT3, and high doses of methylprednisolone and mycophenolate mofetil. CMV disease usually occurs during the first 100 days post-OLT. Recently however, the development of late-onset CMV disease (ocurring after the first 100 days post-OLT), has been reported. Yet, the clinical impact and risk factors of late CMV disease are poorly characterized, and surveillance data beyond the first year is not available.

The Administration of Gliadin Downregulates the Intraepithelial Lymphocytosis Induced by a Rectal Gluten Challenge

Interferon- (IFN-)alpha is currently the standard of care treatment for patients with chronic hepatitis C virus (HCV) infection. A significant part of the benefit of IFN-alpha in chronic hepatitis C is believed to be related to the activation of lymphocytes such as T cells and natural killer (NK) cells, which participate in the elimination of infected cells. Histamine dihydrochloride (HDC) has been shown to potentiate the IFN-alpha-induced activation of T cells and NK cells by a mechanism that involves the protection of these lymphocytes against oxygen radical-induced functional inhibition and apoptosis. This study was designed to examine the efficacy and safety of HDC in combination with IFN-alpha-2b in treatment-naive patients with chronic HCV infection. All patients received IFN-alpha-2b, 3 MIU, three times weekly via subcutaneous injection, and were randomized to one of four HDC regimens (1 mg of either: once a day, three times a week; once a day, five times a week; twice a day, three times a week or; twice a day, five times a week). The doses of HDC in combination with IFN-alpha-2b resulted in sustained viral response rates ranging from 31% to 38%. Sustained biochemical response rates ranged from 28% to 41% across the four treatment groups. Patients infected with HCV genotype 1, and those with high baseline viral levels, which are characteristics associated with poor prognosis, had sustained virologic response rates ranging from 18% to 42% and 15% to 39%, respectively. Combination treatment was generally well tolerated. We propose that the potential benefit of HDC + IFN therapy for chronic HCV infection should be the focus of further investigation.

"Ecstasy" (3,4-Methylenedioxymethamphetamine), is used as a mood enhancer. We describe a case of a 23 year-old male suffering from thrombotic thrombocytopenic purpura (TTP), and severe hepatitis following ingestion of ecstasy. We describe the various hepatic complications, including hepatitis, cirrhosis, and hepatic failure, in addition to the hematological complications including DIC and TTP secondary to ecstasy abuse. Ecstasy abuse should be considered in every patient with unexplained hepatic or hematologic complications.

Vical and Merck are investigating vaccines against hepatitis B which use Vical's patented naked DNA technology. Both therapeutic and prophylactic vaccines are under development [177132], [268397]. The technology, and subsequent collaboration, stems from the observation by Vical that by directly injecting exogenous cDNA into muscle tissue, protein is expressed which gives rise to a strong immune response and protective immunity [163222].

To determine the role of natural killer cell (NK) 1.1+ T cells in pregnancy and in embryo loss.Four groups of C57 mice, consisting of 20 animals each, were studied. Groups A and B included pregnant females treated with anti-NK1.1 monoclonal antibodies until they gave birth or non-NK1.1-depleted antibodies, respectively. In order to evaluate the role of NK1.1+ T cells in pregnancy, female mice in group C were treated with anti-NK1.1 monoclonal antibodies every seven days starting seven days prior to mating until they gave birth. Control mice in group D were not NK1.1-depleted. NK1.1+ T cell depletion was determined by flow cytometric analysis.Depletion of NK1.1+ T cells did not significantly change the pregnancy rate, nor did it significantly alter the number of live births. Numbers of live births tended to decrease in NK1.1-depleted mice, with a mean number of live births of 4.66 as compared with 6.09 in NK1.1-depleted and nondepleted mice, respectively. Similarly, mice treated with anti-NK1.1 monoclonal antibodies every seven days starting seven days prior to mating became pregnant at a rate of 40% as compared with 60% in non-NK1.1-depleted controls. A comparable trend was observed in the number of live births, with a mean number of live births of 5.0 as compared with 6.1 in NK1.1-depleted and non-NK1.1-depleted mice, respectively.In the NK1.1-depleted mouse model, NK1.1+ T cells do not have any direct effect on pregnancy rate or on early embryo loss.

Guillain-Barre and other neurologic syndromes rarely occur as complications of viral hepatitis (A, B and C). Other neurologic syndromes have also been reported in serologically defined viral hepatitis, including mononeuritis, auditory neuritis, and seizures. Chronic hepatitis B and mononeuritis multiplex are found together in 31-54% of patients with periarteritis nodosa. The mechanisms of these associations are unknown, but may include direct cytotoxicity of the virus or immune-mediated damage. Vasculitis of the vasa nervorum plays an intermediate role, at least in some cases. We describe a 36-year-old man with acute non A-G hepatitis complicated by Guillain-Barre syndrome. The neurological manifestation resolved completely without specific therapy within 6 days, as the hepatitis resolved.

Hepatitis B virus (HBV) is a major health problem, with over 300 million HBsAg carriers worldwide. The HBV itself is non-cytopathic, and it is widely accepted that the mechanism of hepatocellular injury is the host anti-viral immune response. Current treatments, including the newly developed therapeutic modalities, are either based on anti-viral drugs or focus on attempts to augment the anti-viral immune response. The results of these approaches have been largely disappointing. There is evidence, however, that subjects with a natural tolerance to HBV or a down-regulated immune response develop little or no liver injury, despite chronic viremia. Lately, it has been shown that it is possible to induce tolerance toward viruses by oral administration of major viral structural proteins. Here, we discuss the pathogenesis of HBV-mediated liver disease and approaches to down-regulate the immune response directed against liver cells by orally inducing tolerance toward the virus. We hypothesize that this acquired tolerance should turn chronic active hepatitis patients with deteriorating disease into ‘healthy’ virus carriers. The proposed new treatment strategy would redirect the focus from augmenting anti-viral immune response to inducing host tolerance towards the virus.

An important consideration in application of hepatocyte transplantation is whether the number of engrafted hepatocytes is sufficient to achieve the desired effect. Here we have evaluated the proliferative potential of transplanted primary hepatocytes during regeneration of hepatic lobes. Two million hepatocytes isolated from congeneic normal Wistar-RHA rats were injected into the main portal vein of deficient, jaundiced Gunn rats. The right branch of the portal vein was ligated 24 hr before hepatocyte transplantation (group A) or transiently clamped during hepatocyte injection (group B) or 24 hr after hepatocyte injection (group C). In these groups, the three lobes supplied by the right branch of the portal vein rapidly atrophied and disappeared in 4 days, whereas the remaining lobes proliferated, as shown by size increase and 5-bromo-2-deoxy-uridine uptake. Two control groups received 2 million (group D) or 20 million hepatocytes (group E) without ligation. Hepatocyte engraftment occurred in all groups. The greatest hypobilirubinemic effect was observed in group A, in which serum bilirubin concentrations were reduced to 1.7+/-0.45 mg/dl from pretransplantation levels of 6.9+/-1.2 mg/dl. This effect was even greater than that observed after transplantation of 20 times more hepatocytes without ligation (group E). Specific endonuclease digestion of a polymerase chain reaction-amplified segment of the ugt1 gene from hepatic DNA showed that up to 25% of the DNA was of donor origin. This paralleled the hepatic bilirubin-UDP-glucuronosyltransferase activity, which was above 50% of normal. The results indicate that the transplanted hepatocytes proliferate preferentially within the regenerating lobes, replacing more than 20% of the liver mass with the progeny of the transplanted phenotypically normal hepatocytes.

The need for solid organ retransplantation is a major factor in the shortage of available organs. Between 1972 and 1992, 56 out of 309 kidney transplants and 2 out of 20 liver transplants performed in our hospital were retransplantations. The present study evaluates local and world experience with organ retransplantations in terms of the medical and ethical issues.

A 54-yr-old man underwent orthotopic liver transplantation for cirrhosis caused by hepatitis C virus and associated with cryoglobulinemia and proteinuria. Four months after transplantation, the patient was reinfected with hepatitis C virus and cryoglobulinemia recurred, accompanied by increasing proteinuria, ascites, and pleural and pericardial effusion. Serum cryoglobulins and pleural and pericardial effusion disappeared rapidly following treatment with ribavirin, whereas proteinuria remain unchanged. We believe that pericardial effusion is an unusual presentation of hepatitis C virus-associated cryoglobulinemia.

Bone marrow transplantation (BMT) has been previously reported as a successful mode of treatment for hepatitis B and associated severe aplastic anemia (SAA). Non-A, non-B, non-C hepatitis is one of the causes of SAA. The etiology of SAA caused by non-A, non-B, non-C hepatitis is unknown. There is evidence that the immune response and, specifically, T cells and monocytes have a major role in both HCV- and HBV-induced liver damage. The liver damage caused by non-A, non-B, non-C hepatitis may be associated with similar mechanisms. We describe an 8-year-old girl who developed SAA post-non-A, non-B, non-C hepatitis infection. She was treated by in vivo CAMPATH-1G antibodies followed by T cell depleted HLA-matched BMT and cyclosporin A, resulting in gradual improvement and almost normalization of liver function. We suggest that treatment with CAMPATH-1G followed by T cell-depleted BMT and cyclosporin A could be a novel mode of therapy for viral non-A, non-B, non-C hepatitis-induced liver damage and associated SAA.

Mixed cryoglobulinemia is well known to be associated with hepatitis C virus (HCV) infection. We report two cases in which cryoglobulinemia appeared or became grossly exacerbated after orthotopic liver transplantation. In both cases, there was co-appearance of cryoglobulinemia with the reinfection of the grafted liver with HCV. It is postulated that the cryoglobulinemia might be related to secondary HCV infection in these patients.

Hepatitis B virus (HBV) reinfection is a major threat to HBV-infected patients undergoing orthotopic liver transplantation. Eleven HBsAg-positive patients with end-stage liver disease underwent liver transplantation. All were treated with high doses of anti-HBs antibodies, initiated first during the anhepatic stage of the operation and continued every 2-8 weeks thereafter according to anti-HBs levels in the serum. Attempts were made to keep anti-HBs levels above 400 IU/ml. Patients were followed for 8-42 months and only one of them had any evidence for recurrence of HBV infection 40 months post-transplantation. We conclude that continuous administration of anti-HBs and maintenance of high levels of anti-HBs in the serum prevent recurrence of HBV infection.

Chimpanzees are currently the only nonhuman animal model for reproducible propagation of hepatitis C virus (HCV). A chimeric mouse model was used for the induction of hepatitis C viremia, using BNX (beige/nude/X-linked immunodeficient) mice preconditioned by total body irradiation and reconstituted with SCID mouse bone marrow cells. HCV-infected liver fragments from patients with HCV RNA-positive sera were transplanted under the kidney capsule of the chimeric mice. HCV-specific RNA sequences were detected by reverse transcriptase nested polymerase chain reaction (RT-PCR) in serum of approximately 50% of grafted animals. In addition, normal liver specimens were incubated with HCV serum and transplanted into chimeric mice, leading to viremia in approximately 25% of animals. Sequential histologic evaluation of the liver implants, from day 2 to week 14 after transplantation, revealed loss of lobular architecture within the implants. However, viremia persisted for 10-50 days after transplantation. These results offer a new HCV model.

Patients undergoing autologous bone marrow transplantation (BMT) are severely immunosuppressed. These patients are exposed to various infections agents due to delayed and efficient reconstitution of their immune system. Forty-eight patients with hemato-oncological malignancies were immunized against hepatitis B virus (HBV) following autologous BMT. Twenty one were vaccinated more than 10 days before BMT, 17 on days 1-9 before and 10 day after BMT. Thirty three patients (68.7%) seroconverted within 40 days after autologous BMT after receiving one dose of the vaccine before autologous BMT with a relatively low level of anti-HBs, whereas in 11 no anti-HBV antibodies could be detected. Nineteen patients remained seropositive but in 11 the seroconversion was only transient no correlation was found between permanent or transient seroconversion and basic disease, conditioning regimens, post-transplant therapy, immunotherapy and day of vaccination in relation to autologous and day of vaccination in relation to autologous BMT. Active HBV immunization of patients with malignancy undergoing autologous BMT is feasible and levels of antibodies, although low, are above the conventional protective titers. Therefore active immunization of some patients may reduce hepatitis-related complications in the setting of autologous BMT.

Clearance of hepatitis B virus (HBV) infection requires an effective T-cell-dependent humoral response that is often defective in HBV carriers and in immunosuppressed patients. We have shown in mice and humans that bone marrow (BM)-derived memory cells, capable of producing antibodies to the HBV envelope and nucleocapsid antigens, are transferable from BM donors (BMD) to their recipients. BMD BALB/c mice were immunized with recombinant HBV surface antigen (HBsAg), and BM from anti-HBs-positive donors was transplanted to irradiated recipient mice, who seroconverted to anti-HBs within 30 days of bone marrow transplantation (BMT), and responded to booster vaccination. In a similar manner, 19/26 human BM recipients, who received their HLA-matched BM from BMDs immunized once with HBsAg, seroconverted within several weeks after BMT. Antibodies to HBsAg were also observed in 3 recipients of peripheral blood lymphocytes (PBL) obtained from HLA-matched immunized human donors. Finally, clearance of HBsAg and HBV DNA was observed in an HBsAg carrier with leukemia who received BMT from his HLA-matched anti-HBc+/anti-HBs+ brother. These results indicate that adoptive transfer of immunity to HBV may be achieved through immunization of BM or PBL donors against HBV.

Orthotopic liver transplantation is now used for children with end-stage liver disease, but the scarcity of size-matched liver allografts for children has limited its use. Reduced-size liver transplantation, in which only part of the liver is used as a graft, overcomes size disparity and increases significantly the potential donor pool for children. A 4-year-old boy with fulminating hepatic failure due to hepatitis became the first case of reduced-size liver transplantation in Israel. A left hepatic lobe allograft from an adult donor was used. The boy is home and well 9 months after transplantation. Reduced-size liver transplantation was first performed in a child by Bismuth and Houssin in 1984. Reports from several centers show that survival of recipients of reduced-size liver allografts and the rate of retransplantation does not differ significantly from that in recipients of full-sized livers.

The prevalence of hepatitis C virus (HCV) infection in patients with chronic liver disease (CLD) in Israel has not yet been reported. A retrospective analysis was performed on the first 92 consecutive patients referred to our Liver Unit with serologically confirmed antibodies to hepatitis C virus (anti-HCV) who had evidence for chronic hepatitis, cirrhosis, and hepatocellular carcinoma. We compared 31 patients who were anti-HCV positive with 61 patients who had evidence for both previous or present infection with hepatitis B virus (HBV) as well as HCV. Dual infection was significantly more prevalent in Jewish patients of non-Ashkenazi origin, who were also characterized by higher rates of portal hypertension manifested by ascites, bleeding esophageal varices as well as hepatic encephalopathy and spontaneous bacterial peritonitis. We conclude that dual infection of HBV and HCV was found in 66% of patients with anti-HCV positive liver disease in Jerusalem, and that these patients develop more serious complications than CLD patients with anti-HCV alone.

Erythrocytosis was found in 20 out of 127 patients who underwent renal transplantation (15.7%). Four were found to have elevated erythropoietin concentrations (139.7 +/- 22.0 microns/ml) and 7 had normal levels (52.3 +/- 84 microns/ml (normal -60). The growth of erythroid CFUs was found to be normal in all patients. Theophylline treatment was given to 11 patients. The patients were divided into 3 groups according to their response: (1) patients with high erythropoietin levels whose hematocrit decreased from 59.6% to 46.3% within 2 weeks of treatment in parallel with a fall in erythropoietin; (2) patients with normal erythropoietin levels in whom theophylline therapy reduced the hematocrit from 58.7% to 47.2%; and (3) patients in whom theophylline had no effect on their erythrocytosis. We conclude that erythrocytosis after renal transplantation is a heterogenous condition and that several mechanisms are involved. In some patients, high erythropoietin levels or high sensitivity to erythropoietin are associated with the erythrocytosis. Theophylline therapy is beneficial in more than 50% of the cases.

Of 10 patients with ulcerative colitis 2 had primary sclerosing cholangitis and 1 had cirrhosis due to chronic active hepatitis. All 3 underwent successful orthotopic liver transplantation due to severe portal hypertension and deteriorating liver function. The interrelations between liver transplantation, immunosuppressive therapy and bowel disease are described.

The idiopathic hypereosinophilic syndrome is a heterogeneous group of disorders characterized by persistent eosinophilia of undetected cause, and multiple organ system involvement. The systems affected include the central and peripheral nervous, cardiovascular, respiratory and gastrointestinal systems and the kidneys, skin, muscles and joints. Treatment is mainly by immunosuppressive drugs to prevent organ system complications. Prognosis is variable, depending mainly on heart involvement.

A 63-year-old patient with sarcoidosis developed a clinical picture compatible with sclerosing cholangitis 20 years later. The uncommon association between these two rare diseases, and possible common pathophysiological-immunological mechanisms are discussed.