David H. Van Thiel

Effect of end-stage liver failure on the incidence and resolution of the adult respiratory distress syndrome☆

Multiple systems organ failure adversely affects outcome in the adult respiratory distress syndrome (ARDS). However, no clinical studies of the influence of preexisting single extrapulmonary organ dysfunction on the incidence and resolution of ARDS have been reported. Hepatic reticuloendothelial system (RES) and hepatic parenchymal cell uptake and detoxification of proinflammatory substances are major elements of systemic host defense and may, accordingly, be important pulmonary defense mechanisms. To better define the effects of liver-lung interactions on the resolution of acute lung injury with preexisting extreme hepatic dysfunction, we retrospectively analyzed the incidence, risk factors, and clinical characteristics of ARDS in 29 patients with end-stage liver failure (ESLF) who required intensive care while awaiting a liver transplantation. We compared data from these patients with those from a concurrent group of 44 intensive care patients without ESLF, and contrasted our findings with recent clinical studies of ARDS predisposition and outcome. ARDS occurred in 23 of 29 patients (79%) with ESLF; sepsis was the most common predisposing risk factor (18 of 29 patients, 62%). ARDS developed in 3 of 44 patients (6.8%) without ESLF (odds ratio comparison with ESLF patients, 42.9, P < .001). Once initiated, regardless of etiology and subsequent ventilatory support, ARDS was uniformly irreversible in all 23 ESLF patients. These findings identify a growing population of critically ill patients at increased risk for nonresolving severe acute lung injury despite current methods of intensive care. We conclude that compromise of systemic and pulmonary defense by impaired hepatic RES performance and hepatocyte function may both predispose to ARDS and critically modulate its resolution.

Quantitation of Estrogen and Androgen Receptors in Hepatocellular Carcinoma and Adjacent Normal Human Liver

Sex hormones have been shown to influence the development and course of several liver diseases. The worldwide predominance of hepatocellular carcinoma (HCC) in males has led to the suggestion that this disease might be hormone-responsive. Therefore, the hepatic estrogen (ER) and androgen receptor (AR) status of liver specimens from such patients was investigated. Samples were obtained from three female and six male patients undergoing liver resection; in each case, a small sample of both the tumor and adjacent normal tissue was collected. All patients had primary hepatocellular carcinoma without cirrhosis. In most cases, the tumor and the normal specimen had an equivalent content of cytosolic ER; however, three of the tumor samples (one female and two male) displayed considerably elevated cytosolic ER levels as compared to that of the normal tissue. In every sample, the tumor contained less nuclear ER than did the normal liver. When AR was measured, tumors of three patients (one female and two male) demonstrated a twofold elevation in cytosolic AR as compared to adjacent normal tissue. In the two male patients, an approximately twofold greater nuclear AR was found. Two other samples from male patients showed a modest elevation of cytosolic AR in the tumors. The patients whose tumors showed elevations in ER were not the same patients as those in whom the AR was elevated. Thus, these studies indicate that certain, but not all, specimens of HCC demonstrate either elevated ER or AR and suggest that a determination of receptor content might be useful prior to initiation of certain antihormone therapies.

Circadian rhythm of hepatic cytosolic and nuclear estrogen and androgen receptors

Mammalian liver is a sex steroid-responsive tissue. The effects of these hormones presumably are mediated by hepatic estrogen receptors (ER) and androgen receptors (AR). Serum levels of sex hormones display circadian rhythms. Further, estrogens and androgens are commonly administered; administration of these agents is associated frequently with liver disease. Therefore, we investigated whether the cytosolic and nuclear sex steroid receptors also display a similar circadian rhythm, and whether variations occurred in the distribution of receptors between cytosolic and nuclear compartments. Animals were killed every 4 h from midnight till the following midnight; cytosolic and nuclear levels of both ER and AR were measured. Cytosolic ER reached a maximum level at 4 AM, and a minimum at 8 PM and midnight of both days. Nuclear ER was highest at 8 AM and lowest at 4 PM and 8 PM, a pattern which parallels variations in serum estradiol levels. Cytosolic AR was highest at 8 PM and lowest at midnight and 4 AM. Nuclear AR was highest at 4 AM and lowest at 4 PM and 8 PM. The highest level of nuclear AR does not correspond to the maximum serum testosterone level, which occurred at 4 PM. The total hepatic content of both ER and AR was not constant over the 24-h period, but varied considerably with time of day. These studies suggest that both ER and AR show a distinct circadian rhythm in subcellular compartmentalization, and that total hepatic content of ER and AR varies significantly during a 24-h period.

Evidence for Autonomous Secretion of Prolactin in Some Alcoholic Men With Cirrhosis and Gynecomastia

Prolactin responses to provocative thyrotropin releasing hormone (TRH) stimulation were evaluated in 20 cirrhotic men with gynecomastia. Fifteen of these cirrhotic men had normal responses with a minimum doubling of the prolactin concentration above basal in response to TRH. Five had abnormal (autonomous) responses in that they failed to double their basal level or had a paradoxical decrease from basal in response to TRH. Moreover, these same five men failed to have a sleep-related increase in plasma prolactin. Three of them also failed to respond to chlorpromazine stimulation. Such abnormal responses are generally associated with the presence of a prolactin secreting pituitary tumor. Basal plasma levels of prolactin were measured in all 20 men studied. The five men who failed to respond to TRH had significantly greater basal prolactin concentrations (80.5 +/- 18.7 ng/ml) than did the 15 men who responded normally (33.7 +/- 4.3 ng/ml) (p less than 0.01), although all 20 had increased prolactin levels relative to that of controls (10.8 +/- 0.9 ng/ml) (both p less than 0.01).

Hyperprolactinemia in portal systemic encephalopathy

The accumulation of false neurotransmitters such as octopamine and depletion of true neurotransmitters such as dopamine have been purported to play a pathogenetic role in portal systemic encephalopathy (PSE). Therefore, we measured plasma prolactin, a known sensitive indicator of functional dopamine activity in man, in an attempt to evaluate dopaminergic function in 21 patients with alcoholic liver disease and PSE and several control groups. Subjects with PSE had markedly elevated prolactin levels (P<0.01) when compared to all control groups. Moreover, patients with PSE were divisible into two groups, 12 having mildly increased prolactin levels and 9 having markedly elevated levels. Although the degree of PSE was similar in both groups, those PSE patients with the higher prolactin values had significantly greater derangement of serum albumin, bilirubin, prothrombin time, and also had a higher mortality (100%). These data: (1) provide evidence consistent with the hypothesis of altered neurotransmitter function in individuals with chronic alcoholic liver disease, particularly those manifesting evidence of PSE; (2) suggest that altered dopamine function in chronic liver disease may have pathophysiologic significance as judged by altered hormone release; (3) demonstrate that a markedly elevated plasma prolactin level in individuals with PSE carries an ominous prognosis; and (4) suggest a possible role for the plasma prolactin in the selection and monitoring of PSE patients who are to be treated with agents aimed at correcting neurotransmitter abnormalities.