Liver complications in inflammatory bowel diseases.

Diseases of the liver and the biliary tract are commonly observed in patients with inflammatory bowel diseases (IBD). Besides primary sclerosing cholangitis (PSC), drug-induced hepatotoxicity and non-alcoholic fatty liver disease (NAFLD) are the most frequent liver complications in IBD. PSC is a chronic inflammatory and commonly progressive disorder of unknown etiology associated with fibrosis and stricture development in the intrahepatic and extrahepatic biliary tree. Interestingly, this form of liver disease is mainly associated with ulcerative colitis. Development of PSC is highly relevant for IBD patients as cholestasis-associated problems increase over time resulting in biliary strictures, cholangitis, cholangiocarcinoma and importantly these patients also have a higher risk to develop colon cancer. Another major aspect regarding IBD and liver disease refers to drug-induced hepatotoxicity. Clinically, most relevant is liver toxicity caused by immunosuppressants such as azathioprine. Azathioprine and its derivate 6-mercaptopurine can cause a spectrum of liver injuries ranging from asymptomatic elevated liver enzymes to cholestasis and nodular regenerative hyperplasia. The third common IBD-associated liver disease is NAFLD, and first studies suggest that NAFLD might appear in IBD patients independent of classical risk factors such as obesity or insulin resistance. Overall, liver complications are observed in 10-20% of IBD patients, and therefore physicians have to be familiar with these complications to improve and to optimize patient care.

Targeting T and B lymphocytes in inflammatory bowel diseases: lessons from clinical trials.

Both innate and adaptive immunity play an important role in the pathogenesis of inflammatory bowel diseases (IBDs). There is strong evidence that especially activated T cells initiate and perpetuate inflammation and tissue destruction. The increased numbers of CD4+ T cells in the intestinal wall of IBD patients may be explained by enhanced influx/activation and decreased apoptosis of these cells. Several studies have demonstrated that the gut-homing receptors CCR9 and α4ß7 are selectively induced on T cells during their priming in intestinal inflamed sites. Whereas targeting of activated CD4+ T cells by specific antibody strategies or neutralization of key T-cell cytokines such as IL-2 or IFN-γ has not been effective in human IBD, blocking migration of activated leukocytes, e.g. T cells into the inflamed tissue by specific antibodies such as vedolizumab, seems highly effective. Recently it could also been demonstrated that administration of antigen-specific regulatory T cells to patients with refractory Crohn's disease was not only well tolerated but showed promising results. The role of B cells in human IBD is less clear. B-cell depletion has so far only been studied in ulcerative colitis where rituximab (anti-CD20) therapy failed. Therefore, although the therapeutic targeting of 'inflammatory' T and B cells was not successful in IBD, especially T cells remain key players in IBD. Targeting either T-cell migration or the use of regulatory T cells appears as the most promising 'T-cell-directed' therapies in the future.

beta-Endorphin. Intravenous infusion causes behavioral change in psychiatric inpatients.

Ten depressed and eight schizophrenic patients received synthetic human beta-endorphin infusions in a double-blind, placebo-controlled, crossover design. Physicians' and nurses' ratings and patients' self-ratings were used to measure behavioral change. Depressed patients improved significantly two to four hours after beta-endorphin treatment when compared with placebo treatment. There was no significant change in the schizophrenic patients as a group, although six of eight worsened after beta-endorphin treatment. No significant behavioral effects were observed during the infusions themselves or on postinfusion days.

Cerebral metabolic rates for glucose in mood disorders. Studies with positron emission tomography and fluorodeoxyglucose F 18.

Cerebral metabolic rates for glucose were examined in patients with unipolar depression (N = 11), bipolar depression (N = 5), mania (N = 5), bipolar mixed states (N = 3), and in normal controls (N = 9) using positron emission tomography and fluorodeoxyglucose F 18. All subjects were studied supine under ambient room conditions with eyes open. Bipolar depressed and mixed patients had supratentorial whole brain glucose metabolic rates that were significantly lower than those of the other comparison groups. The whole brain metabolic rates for patients with bipolar depression increased going from depression or a mixed state to a euthymic or manic state. Patients with unipolar depression showed a significantly lower ratio of the metabolic rate of the caudate nucleus, divided by that of the hemisphere as a whole, when compared with normal controls and patients with bipolar depression.

Effects of a dopamine agonist piribedil in depressed patients: relationship of pretreatment homovanillic acid to antidepressant response.

Piribedil, a compound that stimulates dopamine receptors in a relatively specific fashion, was administered to 11 hospitalized depressed patients. The dopamine agonist significantly decreased rapid eye movement (REM) sleep and percent REM sleep and increased REM latency. Piribedil decreased the probenecid-induced accumulation of the dopamine metabolite homovanillic acid (HVA) in CSF. A range of mild to moderate antidepressant effects was noted; one patient worsened and one developed recurrent manic episodes. The degree of improvement in depression was negatively correlated with pretreatment values of HVA in CSF (r = -.66, P less than .05). These data suggest that the heterogeneity of clinical response may be related to biological differences in depressed patients and that those with low initial dopaminergic function respond best to increased dopamine receptor stimulation.

Reduction of prefrontal cortex glucose metabolism common to three types of depression.

Using positron emission tomography, we studied cerebral glucose metabolism in drug-free, age- and sex-matched, right-handed patients with unipolar depression (n = 10), bipolar depression (n = 10), obsessive-compulsive disorder (OCD) with secondary depression (n = 10), OCD without major depression (n = 14), and normal controls (n = 12). Depressed patients were matched for depression on the Hamilton Depression Rating Scale, and subjects with OCD without depression and OCD with depression had similar levels of OCD without depression and OCD with depression had similar levels of OCD pathology. We also studied six non-sex-matched patients with mania. Mean (+/- SD) glucose metabolic rates for the left dorsal anterolateral prefrontal cortex, divided by the rate for the ipsilateral hemisphere as a whole (ALPFC/hem), were similar in the primary depressions (unipolar depression = 1.05 +/- 0.05; bipolar depression = 1.04 +/- 0.05), and were significantly lower than those in normal controls (1.12 +/- 0.06) or OCD without depression (1.15 +/- 0.05). Results for the right hemisphere were similar. Values in subjects with OCD with depression (1.10 +/- 0.05) were also significantly lower than in subjects with OCD without depression, and values in subjects with bipolar depression were lower than those in manic subjects (1.12 +/- 0.03) on this measure in the left hemisphere, although results were not significant in the right hemisphere. There was a significant correlation between the HAM-D score and the left ALPFC/hem. With medication for depression (n = 12), the left ALPFC/hem increased significantly and the percentage change in the Hamilton scale score correlated with the percentage change in the left ALPFC/hem.(ABSTRACT TRUNCATED AT 250 WORDS)

Lithium does not inhibit the parathyroid hormone-mediated rise in urinary cyclic AMP and phosphate in humans.

To test the hypothesis that lithium is a general inhibitor of hormone-activated adenylate cyclase, we infuse parathyroid hormone (PTH) into human subjects prior to and during lithium carbonate administration. PTH infusion caused a significant increase in urinary cyclic AMP and urinary phosphate excretion. There was no significant difference in these responses in the lithium compared to the control period. In four patients with primary hyperparathyroidism, lithium had no significant effect on serum calcium or phosphate or on tubular reabsorption of phosphate. The data do not substantiate the hypothesis that lithium (at therapeutic concentrations) is a general inhibitor of hormonally-activated adenylate cyclase, nor do they support its potential clinical utility in primary hyperparthyroidism.

Intravenous infusion of beta-endorphin increases serum prolactin, but not growth hormone or cortisol, in depressed subjects and withdrawing methadone addicts.

In a randomized, double blind, cross-over study, human beta-endorphin or saline was infused iv over 30 min into six depressed psychiatric patients and four methadone addicts. All depressed subjects showed prompt, 2- to 4-fold increases in serum PRL levels, which lasted at least 2 h. The addicts, who were undergoing acute methadone withdrawal, showed similar PRL increases, which were dose dependent. beta-Endorphin did not increase serum levels of cortisol or GH in either group of subjects. These results suggest that iv beta-endorphin has potent but selective neuroendocrine effects in depressed patients and subjects withdrawing from methadone.

Neurochemical abnormalities in anorexia nervosa: similarities to affective disorders.

Certain investigators have asserted that the illness of anorexia nervosa is a form of hypothalamic disturbance. The relationship between 24-hr urine 3-methoxy-4-hydroxyphenylglycol (MHPG) and dexamethasone suppression tests was examined in 13 female patients with AN diagnosed by RDC. Patients showed a consistent association between low urine MHPG and failure to suppress to dexamethasone. In addition, family histories of index cases showed a high percentage of relatives with either primary affective disorder or alcoholism. These results are evidence in support of an hypothesis of hypothalamic dysfunction in AN. Furthermore, these biochemical parameters are also found to be abnormal in PAD. These data, coupled with the genetic material, suggest a link between AN and PAD.

The effects of sleep deprivation on average evoked responses in depressed patients and in normals.

The effects of a single night of sleep deprivation on the amplitude and amplitude/stimulus intensity function of the visual evoked potential (EP) were studied in 16 patients with primary affective disorder and 20 normal controls. Visual EP amplitude and amplitude/intensity slopes tended to increase after sleep deprivation in the patient group, a direction found in other studies to be associated with a spontaneous mood improvement and changes with antidepressant medication. In contrast, normal volunteers who showed little or no mood elevation showed generally opposite EP effects. Taken together, the results suggest a similarity in the neurophysiological effect of sleep deprivation between patient and antidepressant medication in depressed patients.

Central tryptamine turnover in depression, schizophrenia, and anorexia: measurement of indoleacetic acid in cerebrospinal fluid.

There has been a continuing interest in the possible role of the trace amine tryptamine in the etiology of neuropsychiatric disorders. We have therefore examined cerebrospinal fluid (CSF) levels of indole-3-acetic acid (IAA), the major metabolite of tryptamine, in a large group of normals and in several patient populations. No differences in CSF IAA levels (ng/ml, mean +/- SEM) were observed between normals (4.39 +/- 0.37, n = 36), anorectics (4.40 +/- 0.42, n = 35), schizophrenics (4.06 +/- 0.05, n = 17), manics (4.32 +/- 0.63, n = 10), or depressives (5.23 +/- 0.49, n = 39). A significant elevation (p = 0.05) was found in the subgroup of retarded depressives (RDC) where levels of 5.90 +/- 0.80 (n = 19) were observed. An age effect (r = 0.39, p = 0.02, n = 36) was observed in normals; however IAA was not reduced to either height or weight. IAA tended to be higher (but not significantly) in females in all groups studied; this difference also was not significant when all diagnostic groups (except anorectics) were combined (female: 4.95 +/- 0.44, n = 45; male: 4.46 +/- 0.30, n = 66). In general, the results indicate that tryptamine turnover is not altered in the disorders studied. The functional significance of the slight elevation seen in retarded depressives is not clear.

Relationship between EEG sleep patterns and clinical improvement in depressed patients treated with sleep deprivation.

The effects of a single night of total sleep deprivation were observed in 16 primary depressed patients. Responders to treatment were rated as significantly more depressed and revealed a more "depressed" EEG sleep pattern prior to sleep deprivation than did nonresponders. Following sleep deprivation, patients who improved experienced a rebound in REM sleep during the second night of recovery sleep.

Decreased seasonal mesor of platelet 3H-imipramine binding in depression.

Seasonal cycles of platelet 3H-imipramine binding were compared in 49 endogenous unipolar depressed patients and 20 normal volunteers. A significant sinusoidal component was detected in the Bmax of binding in both patients and controls with similar amplitudes and seasonal peaks. However, the yearly average (mesor) of the patient group was significantly lower (20.0%) than that of the normal controls. The results support earlier claims of a diminished platelet binding in endogenous depression and indicate that this decrease was still evident in the presence of a 48.2% (controls) to 65.8% (patients) seasonal variation. Control Bmax values were normally distributed about a best-fit mean (cosinor fit). In contrast, patient values appeared to be bimodally distributed with one mode that was similar to controls and one mode that was substantially lower. In general, psychiatric symptoms failed to distinguish between patients with high and low platelet binding and no correlation was found between Bmax and severity of illness (HAM-D).

Changes in platelet 3H-imipramine binding with chronic imipramine treatment are not state-dependent.

One month of imipramine treatment increased both the Kd and Bmax of platelet 3H-imipramine binding in 11 endogenous unipolar depressed patients. Continued treatment (13 weeks) of 5 patients subsequently lowered the Bmax values of 2 patients who had initially shown the largest increases, so that binding was no longer significantly elevated after 13 weeks. The observed changes in Kd but not in Bmax, could be explained by the carryover of tightly bound drug to the binding assay, although neither of the measures were correlated with plasma imipramine levels. Posttreatment Bmax (4 weeks) values were inversely related to plasma cortisol levels, although a weak but positive correlation was found before treatment. No significant change was found in plasma cortisol with treatment. Clinical responses were not related to cortisol or Bmax changes, although optimal improvement was associated with extreme values (high and low) of pretreatment Bmax. The present results, obtained with imipramine, and similar results obtained after nortriptyline and electroconvulsive shock by others, suggest that at least some antidepressants may induce transient changes in the Bmax of platelet binding that are independent of affective state.

An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia.

BACKGROUND: Hippocampal atrophy has been described in postmortem and magnetic resonance imaging studies of schizophrenia. The specificity of this finding to schizophrenia remains to be determined. The neuropathology of bipolar disorder is understudied, and temporal lobe structures have only recently been evaluated. METHODS: Twenty-four bipolar, 20 schizophrenic, and 18 normal comparison subjects were evaluated using magnetic resonance brain imaging. Image data were acquired using a three-dimensional spoiled GRASS sequence, and brain images were reformatted in three planes. Temporal lobe structures including the amygdala, hippocampus, parahippocampus, and total temporal lobe were measured to obtain volumes for each structure in the three subject groups. Severity of symptoms in both patient groups was assessed at the time the magnetic resonance images were obtained. RESULTS: Hippocampal volumes were significantly smaller in the schizophrenic group than in both bipolar and normal comparison subjects. Further, amygdala volumes were significantly larger in the bipolar group than in both schizophrenic and normal comparison subjects. CONCLUSIONS: The results suggest differences in affected limbic structures in patients with schizophrenia and bipolar disorder. These specific neuroanatomic abnormalities may shed light on the underlying pathophysiology and presentation of the two disorders.

CSF cortisol in patients with depression, mania, or anorexia nervosa and in normal subjects.

The authors studied CSF cortisol in 30 depressed patients, 10 manic patients, 21 women with anorexia nervosa, and 22 normal control subjects. All patients were also rated on a global severity scale for mania or depression. Results indicated higher CSF cortisol levels in all three patient groups than in the control group. Only the depressed group had a significant positive correlation between CSF cortisol and severity ratings. The authors recommend further research into the hypothalamic mechanisms associated with cortisol secretion and regulation.

CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa.

The authors examined the CSF GABA of 87 subjects: 29 normal control subjects, 11 patients with schizophrenia, 26 with depression, 6 with mania, and 15 with anorexia nervosa. Depressed patients had significantly lower CSF GABA levels than did normal subjects. This finding suggests that GABA may have a direct or indirect association with depressive affective disorders.

Abnormalities of dexamethasone suppression test and urinary MHPG in anorexia nervosa.

Twenty-two patients with primary anorexia nervosa were assessed on variables of weight, mood, dexamethasone suppression test, and 24-hour urinary MHPG levels. Patients at less than 80% of their ideal weight had abnormally high cortisol levels after the test and low MHPG levels, regardless of their mood. The authors hypothesize that these abnormalities are not due to depression associated with anorexia nervosa and that decreased norepinephrine metabolism may be related to this illness.

Results of clinical renal function tests in lithium patients.

Because there have been reports suggesting that patients who receive lithium are at risk for renal damage, the authors carried out extensive noninvasive testing of renal function in 43 patients who had been taking lithium for from 1 to 120 months. Their only abnormal finding was that the urine concentrating ability of these patients was moderately but asymptomatically impaired. They suggest that although patients receiving lithium should be carefully evaluated and tested, there is not enough evidence to justify not initiating or continuing lithium use in patients who might benefit from it.

The dexamethasone suppression test and response to methylphenidate in depression.

The authors studied 19 inpatients with major depressive episode or schizoaffective disorder, depressed type, and compared their response to the dexamethasone suppression test (DST) with their response to the methylphenidate stimulation test. They found a significant negative correlation between responses to DST and to methylphenidate.