Medullary thyroid cancer with ectopic Cushing's syndrome: A multicentre case series.

OBJECTIVE: Ectopic Cushing's syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. DESIGN: Retrospective cohort study in three German and one Swiss referral centres. PATIENTS: Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. MEASUREMENTS: The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. RESULTS: The median age at diagnosis of ECS was 59 years (range: 35-81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0-193). Median serum morning cortisol was 49 µg/dl (range: 17-141, normal range: 6.2-18). Eight (73%) patients received treatment for ECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval [95% CI]: 64-111) than matched controls (190 months, 95% CI: 95-285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. CONCLUSION: This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case.

[Diagnostic workup of adrenal masses]. / Diagnostik von Raumforderungen in der Nebenniere.

With the increasing use of abdominal imaging, adrenal masses are more frequently detected. Depending on the clinical context, the detection of an adrenal mass has different consequences for downstream testing and therapy. As adrenal masses comprise various benign and malignant aetiologies, all lesions >1 cm need further diagnostic workup. Evaluation should address radiological features with respect to potential malignancy and endocrine activity of the lesion. The majority of adrenal masses are benign, functionally inactive adenomas that need no further therapy or follow-up. Nonetheless, functional adenomas, pheochromocytomas, metastases, adrenal cancer or others account for a relevant proportion of lesions. To determine an appropriate therapy, suspicious, malignant or hormonally active tumours should be discussed in an interdisciplinary tumour board. In case of surgery of a lesion with concomitant hormonal excess, perioperative management needs to be guided by the specific requirements of this entity to avoid increased morbidity and mortality.

Analysis of IL2/IL21 gene variants in cholestatic liver diseases reveals an association with primary sclerosing cholangitis.

BACKGROUND/AIMS: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. METHODS: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. RESULTS: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). CONCLUSION: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC.

Medical treatment of primary sclerosing cholangitis: a role for novel bile acids and other (post-)transcriptional modulators?

Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease of the liver and bile ducts that is associated with inflammatory bowel disease, generally leads to end-stage liver disease, and is complicated by malignancies of the biliary tree and the large intestine. The pathogenesis of PSC remains enigmatic, making the development of targeted therapeutic strategies difficult. Immunosuppressive and antifibrotic therapeutic agents were ineffective or accompanied by major side effects. Ursodeoxycholic acid (UDCA) has consistently been shown to improve serum liver tests and might lower the risk of colon carcinoma and cholangiocarcinoma by yet unknown mechanisms. Whether "high dose" UDCA improves the long-term prognosis in PSC as suggested by small pilot trials remains to be demonstrated. The present overview discusses potential therapeutic options aside of targeted immunological therapies and UDCA. The C23 bile acid norUDCA has been shown to markedly improve biochemical and histological features in a mouse model of sclerosing cholangitis without any toxic effects. Studies in humans are eagerly being awaited. Nuclear receptors like the farnesoid-X receptor (FXR), pregnane-X receptor (PXR), vitamin D receptor (VDR), and peroxisome-proliferator-activator receptors (PPARs) have been shown to induce expression of diverse carriers and biotransformation enzymes of the intestinal and hepatic detoxification machinery and/or to modulate fibrogenesis. Pros and cons of respective receptor agonists for the future treatment of PSC are discussed in detail. In our view, the novel bile acid norUDCA and agonists of PPARs, VDR, and PXR appear particularly attractive for further studies in PSC.

Long-term LDL apheresis does not stably improve hemorheology in hypercholesterolemic patients with coronary artery disease.

Hemorheological abnormalities are independent cardiovascular risk indicators and adversely affect the outcome of cardiovascular disease. Single LDL apheresis treatment was shown to improve blood and plasma viscosity, red cell aggregation and deformability. However, the long-term effects of LDL apheresis on hemorheology are still unknown. Therefore, we investigated hemorheological parameters in 23 patients (11 women, 12 men) with angiographically established coronary heart disease and drug-resistant hypercholesterolemia regularly treated with LDL apheresis for 7.6+/-3.1 years. Hemorheological measurements (whole blood viscosity, plasma viscosity, red blood cell aggregation at stasis and low shear rate) were analyzed in all patients before and after the initial LDL apheresis as well as before a current LDL apheresis. Single LDL apheresis resulted in significantly reduced plasma viscosity, whole blood viscosity and erythrocyte aggregation index. However, long-term apheresis had no sustained effect on plasma and whole blood viscosity. Our data indicate that in contrast to its beneficial short-term effects, long-term LDL apheresis does not stably improve hemorheology.

Tauroursodeoxycholic acid reduces bile acid-induced apoptosis by modulation of AP-1.

Ursodeoxycholic acid (UDCA) is used in the therapy of cholestatic liver diseases. Apoptosis induced by toxic bile acids plays an important role in the pathogenesis of liver injury during cholestasis and appears to be mediated by the human transcription factor AP-1. We aimed to study if TUDCA can decrease taurolitholic acid (TLCA)-induced apoptosis by modulating AP-1. TLCA (20 microM) upregulated AP-1 proteins cFos (26-fold) and JunB (11-fold) as determined by quantitative real-time PCR in HepG2-Ntcp hepatoma cells. AP-1 transcriptional activity increased by 300% after exposure to TLCA. cFos and JunB expression as well as AP-1 transcriptional activity were unaffected by TUDCA (75 microM). However, TUDCA significantly decreased TLCA-induced upregulation of cFos and JunB. Furthermore, TUDCA inhibited TLCA-induced AP-1 transcriptional activity and reduced TLCA-induced apoptosis. These data suggest that reversal of bile acid-induced AP-1 activation may be relevant for the antiapoptotic effect of TUDCA in liver cells.

Free fatty acids sensitize hepatocytes to bile acid-induced apoptosis.

Delivery of free fatty acids to the liver in nonalcoholic fatty liver disease (NAFLD) may render hepatocytes more vulnerable to glycochenodeoxycholic acid (GCDCA)-induced apoptosis. Fat overloading was induced in HepG2-Ntcp cells and primary rat hepatocytes by incubation with palmitic or oleic acid. Apoptosis was quantified by measuring caspase 3/7 activity and transcription of interleukin (IL) 8 and IL-22 by quantitative real-time PCR. Oleic acid (500 microM) alone did not induce apoptosis, while palmitic acid (500 microM) increased apoptosis 5-fold. GCDCA did not induce significant apoptosis at low micromolar concentrations (5-30 microM) in non-steatotic cells. However, at the same concentrations, GCDCA increased apoptosis 3-fold in oleic acid-pretreated HepG2-Ntcp cells and 3.5-fold in primary rat hepatocytes. Pretreatment with oleic acid increased GCDCA-induced gene transcription of the proinflammatory cytokines IL-8 and IL-22 5-fold and 19-fold, respectively. Thus, low levels of cholestasis normally not considered harmful could advance liver injury in patients with NAFLD.

Medical treatment of cholestatic liver disease.

In most cholestatic liver diseases the cause of the disease is not known and therapy can only be directed toward suppression of the pathogenetic processes and amelioration of the consequences of cholestasis. The recognition of adaptive-compensatory responses to cholestasis has become of major importance. They tend to minimize retention of bile acids and other potentially toxic solutes in the hepatocyte by limiting hepatocellular uptake, reducing bile acid synthesis, stimulating detoxification, and up-regulating alternative pathways for excretion. Some of the drugs used for the treatment of cholestatic liver diseases in an empiric way turned out to be modulators of nuclear receptors, which regulate these adaptive-compensatory responses. New drugs are being designed and tested along these lines and may be regarded as treatment opportunities of the future.

Pathogenesis and treatment of pruritus in cholestasis.

Pruritus is an enigmatic, seriously disabling symptom accompanying cholestatic liver diseases and a broad range of other disorders. Most recently, novel itch-specific neuronal pathways, itch mediators and their relevant receptors have been identified. In addition, new antipruritic therapeutic strategies have been developed and/or are under evaluation. This review highlights recent experimental and clinical findings focusing on the pathogenesis and actual treatment of pruritus in cholestatic liver disease. Evidence-based therapeutic recommendations, including the use of anion exchange resins cholestyramine, colestipol and colesevelam, the microsomal enzyme inducer rifampicin, the opioid receptor antagonists naltrexone and naloxone, and the serotonin reuptake inhibitor sertraline, are provided.

Ursodeoxycholic acid treatment of vanishing bile duct syndromes.

Vanishing bile duct syndromes (VBDS) are characterized by progressive loss of small intrahepatic ducts caused by a variety of different diseases leading to chronic cholestasis, cirrhosis, and premature death from liver failure. The majority of adult patients with VBDS suffer from primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA), a hydrophilic dihydroxy bile acid, is the only drug currently approved for the treatment of patients with PBC, and anticholestatic effects have been reported for several other cholestatic syndromes. Several potential mechanisms of action of UDCA have been proposed including stimulation of hepatobiliary secretion, inhibition of apoptosis and protection of cholangiocytes against toxic effects of hydrophobic bile acids.

Malacoplakia in a renal transplant recipient.

Malacoplakia is a rare, inflammatory condition characterized histologically by distinct histiocytes with pathognomonic inclusion calcospherules called Michaelis-Gutmann bodies. It most often affects the urinary tract of immunocompromised patients. We describe a case of renal allograft parenchymal malacoplakia in a transplant recipient. Moreover, we report the imaging and histological findings and review the literature of this rare disorder.

[Causes, diagnosis and differential diagnosis of hyponatremia]. / Hyponatriämie.

Hyponatremia is a common electrolyte disorder that arises from disturbances in water metabolism. In cases of acute advanced hyponatremia, serious symptoms are predominant, while chronic mild hyponatremia causes minor symptoms such as slowness, depression or unsteadiness of gait. Any therapy of hyponatremia depends on the severity of its symptoms and on its specific etiology and diagnosis. Concerning the differential diagnosis of the type of hyponatremia, it is initially helpful to distinguish between euvolemic, hypervolemic and hypovolemic forms of hyponatremia. In order to distinguish between these 3 types of hyponatremia, it is best to assess the spontaneous urinary sodium concentration and to consider evidence from the medical history and the physical examination. Once the type of hyponatremia has been diagnosed, the next step is to decide which of the known etiologies of hyponatremia applies. Diagnostic problems may arise in mixed hyponatremia, a condition in which different types and etiologies of hyponatremia occur at the same time. In such cases it may be best to determine what appears to be the leading diagnosis. Another kind of diagnostic difficulty often occurs in simultaneous diuretic use. It may help to distinguish to which extracellular volume the types of hyponatremia relate on the basis of the fractional excretion of uric acid rather than on the urinary sodium concentration.

Extrahepatic manifestations of cholestatic liver diseases: pathogenesis and therapy.

Pruritus, fatigue, and metabolic bone disease are frequent complications of cholestatic liver diseases, which can be quite distressing for the patient and can considerably reduce the quality of life. The molecular pathogenesis of these extrahepatic manifestations of cholestasis is poorly understood, and hypotheses to explain these symptoms are being discussed. This article provides treatment recommendations for the complications of cholestasis based on putative pathomechanisms and summarizes recent experimental and clinical data involving management options.

ABCB4 deficiency: A family saga of early onset cholelithiasis, sclerosing cholangitis and cirrhosis and a novel mutation in the ABCB4 gene.

Gallstones are very common. However, there is a small group of patients with low phospholipid-associated cholelithiasis (LPAC) that is characterized by symptomatic cholelithiasis at a young age (<40 years), recurrence of biliary symptoms despite cholecystectomy and concrements or sludge in the intra- and extrahepatic biliary system. The LPAC syndrome is associated with mutations of the adenosine triphosphate-binding cassette, subfamily B, member 4 (ABCB4) gene encoding the hepatobiliary phospholipid translocator multidrug resistance protein 3 (MDR3). Impairment of MDR3 leads to a reduction of biliary phosphatidyl choline levels resulting in a lithogenic and toxic bile. This causes recurrent cholelithiasis, continuous irritations of the biliary tract with cholangitis, chronic cholestasis and even biliary cirrhosis. Here we report on a family with ABCB4 deficiency and LPAC syndrome associated with a novel mutation (c.3203T>A) in the ABCB4 gene.

Primary biliary cirrhosis following Lactobacillus vaccination for recurrent vaginitis.

BACKGROUND/AIMS: Antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex, PDC-E2, and other mitochondrial 2-oxoacid dehydrogenases (AMA-M2) are the hallmark for diagnosis of primary biliary cirrhosis (PBC). AMA-M2 formation as an early step in the pathogenesis of PBC has recently been assumed to be triggered by bacterial mimics of the E2 subunit and certain reactant xenobiotics. We report a case of symptomatic PBC diagnosed after sequential immunization with a lactobacillus vaccine for recurrent vaginitis over years. METHODS: Serum AMA-M2 specificity of the patient was evaluated by indirect immunofluorescence, immunoblotting and ELISA. Serum antibody responses against pyruvate dehydrogenase complex-E2 subunit (PDC-E2(212-226)), the major PBC-specific mitochondrial autoepitope, and microbial mimics revealed cross-reactivity with beta-galactosidase of Lactobacillus delbrueckii (LACDE BGAL(266-280)) which shows a high local homology with that of Lactobacillus species administered via the vaccine. The relative affinity of antibody reactivity to LACDE BGAL(266-280) was significantly higher than that against human PDC-E2(212-226). CONCLUSIONS: We conclude that lactobacillus vaccination therapy may be another culprit for the development of PBC in genetically susceptible women.