Addisonian crisis in a liver transplant patient due to fluconazole withdrawal.

Fluconazole is an antifungal agent commonly used in liver transplant patients. In addition to its antifungal activity, it is a potent inhibitor of the liver cytochrome P450 enzymes. These enzymes degrade a wide range of metabolically active compounds including glucocorticoids. In this report, we identify an episode of Addisonian crisis that occurred in a liver transplant patient receiving prednisone immunosuppression after fluconazole was discontinued. We postulate the mechanism for the crisis was a reversal of the fluconazole-induced suppression of the P450 enzymes. The resulting increased activity altered the patient's glucocorticoid metabolism leading to an Addisonian crisis.

Nefazodone-induced liver failure: report of three cases.

BACKGROUND: Liver failure is a rare but devastating result of drug toxicity. OBJECTIVE: To describe three cases of subfulminant liver failure that were probably caused by nefazodone, a new antidepressant that is a synthetically derived phenylpiperazine. DESIGN: Case series. SETTING: Two university medical centers and a children's hospital. PATIENTS: Three women 16 to 57 years of age. INTERVENTION: Two patients underwent liver transplantation; the third was listed for transplantation but subsequently improved. MEASUREMENT: Liver biopsy. RESULTS: Nefazodone was administered for 14 to 28 weeks before the onset of symptoms. The duration of jaundice before onset of encephalopathy ranged from 4 to 6 weeks. All cases of liver failure had similar histologic appearance, with prominent necrosis in the centrolobular areas (zone 3). One patient had successful liver transplantation, one underwent transplantation but died, and one improved without transplantation. The temporal onset of disease after the start of nefazodone therapy suggested severe hepatocellular injury caused by the drug. CONCLUSIONS: Because nefazodone seems to cause severe hepatocellular injury in an idiosyncratic manner, routine liver chemistries should be performed before starting nefazodone therapy and patients should be monitored regularly. Therapy should be discontinued if liver enzyme concentrations become abnormal.

Microsatellite instability is absent in liver and biliary mucosa of patients with primary sclerosing cholangitis.

Microsatellite instability occurs in the colonic mucosa of patients with inflammatory bowel disease and may predispose the mucosa to neoplastic transformation. It is unknown whether microsatellite instability also plays a role in the neoplastic risk associated with primary sclerosing cholangitis. We examined 134 tissue samples from 21 patients with sclerosing cholangitis for microsatellite instability at eight loci. All tissues were also stained immunohistochemically using an antibody to the proliferation marker Ki-67. Microsatellite instability did not occur in any samples from the intrahepatic or extrahepatic biliary system, although one patient demonstrated instability in the colon. Ki-67 indices ranged from 0 to 2.5 in nondysplastic biliary epithelium and from 1.5 to 29.4 in areas of dysplasia. The absence of microsatellite instability in sclerosing cholangitis suggests that the genetic basis of neoplastic progression in chronic inflammatory disease of the bile ducts differs from that of intestinal cancers arising in the setting of chronic inflammatory bowel disease and may relate to differences in the microenvironment in these two sites.

Rimantadine for treatment of hepatitis C infection in liver transplant recipients.

Hepatitis C recurrence after liver transplantation is a serious problem, leading to increased graft loss and morbidity in some individuals. Treatment with interferon and other agents is controversial and not highly efficacious. The use of an effective antiviral agent to reduce or eliminate viral burden is desirable. To this end, we performed an open-label pilot trial to determine if rimantadine would show antiviral activity against hepatitis C virus (HCV) in the posttransplantation setting. Eleven patients with recurrent post-liver transplantation disease, characterized by transaminase level abnormality and HCV RNA in serum and liver biopsy specimens consistent with HCV infection were offered enrollment onto the study. Patients were treated for 12 weeks with rimantadine, 100 mg orally twice daily, and followed up after treatment for up to 8 additional weeks. Serum was collected at 2-week intervals to assess transaminase and HCV RNA levels. Nine patients completed the planned course of therapy. There was no significant change in serum alanine aminotransferase levels during treatment. No patients cleared HCV RNA from the serum, and fluctuations in the viral titer were not clearly associated with the initiation and completion of the active-treatment phase. Rimantadine was well tolerated, with only one patient who stopped therapy for perceived side effects. We conclude that rimantadine monotherapy has no role in the management of recurrent hepatitis C after liver transplantation.

Combination therapy with thymosin alpha1 and interferon for the treatment of chronic hepatitis C infection: a randomized, placebo-controlled double-blind trial.

Hepatitis C is a major cause of liver disease leading to cirrhosis. Although interferon (IFN) is the only approved therapy, treatment is characterized by low response rates and dose-limiting side effects. We evaluated the addition of thymosin alpha1 (TA1), an immunomodulatory peptide, to the standard treatment regimen for hepatitis C to determine if combination therapy shows biological activity using outcome measures including normalization of alanine aminotransferase levels, histological activity, and viral load during treatment. We performed a randomized, double-blind, placebo-controlled trial to compare the biological activity of a combination TA1 and IFN with that seen for IFN alone in patients with chronic hepatitis C infection. One hundred nine patients were randomized for intention to treat and received 1.6 mg of TA1 subcutaneously twice weekly and 3 MU of IFN three times weekly; 3 MU of IFN three times weekly and placebo TA1; or placebo for both agents. All patients had chronic HCV infection with confirmation of chronic hepatitis on liver biopsy. Biochemical responders were followed up until alanine aminotransferase (ALT) levels became abnormal or for 26 weeks, and relapsers were retreated for 26 weeks in the same treatment arm. One hundred three patients completed treatment for 26 weeks, and six patients dropped out. The groups were similar with regard to sex, gender distribution, baseline histological activity index (HAI) score, risk factors, and viral titers. End-of-treatment biochemical response was seen in 37.1% of patients treated with combination therapy, 16.2% of patients treated with IFN alone, and 2.7% of untreated controls by intent-to-treat analysis (IFN/TA1 vs. IFN, chi2 = 4.05, P = .04). HCV RNA clearance was seen in 37.1% of IFN/TA1-treated patients and 18.9% of IFN-treated subjects. Mean HCV RNA titers were significantly lower than baseline at weeks 8, 16, and 24 after drug initiation among patients treated with IFN/TA1 but not in the other treatment arms. Histological improvement, as evidenced by a decrease in HAI of more than two points, occurred in the combination therapy arm more frequently than in comparison groups. Cumulative sustained biochemical responses were 14.2% and 8.1% in the IFN/TA1 and IFN arms, respectively, based on an intention-to-treat model. The combination of TA1 and standard IFN treatment for chronic hepatitis C showed evidence of biological activity at the completion of treatment by biochemical, histological, and virological outcome measures. Further research involving longer duration and varied dosing is needed.

Effects of lactulose on nitrogen metabolism.

Lactulose is the most frequently utilized agent in the treatment of hepatic encephalopathy because of its efficacy and the fact that it has few serious side effects. How this non-absorbable disaccharide works has been a matter of controversy, but evidence suggests that metabolism by the enteric flora is necessary for its mechanism of action. When the intestinal flora metabolizes lactulose, bacterial incorporation of nitrogen increases, as does the bacterial mass. The presence of a carbohydrate and the acidic environment caused by the production of organic acids also act to reduce the breakdown of other nitrogen-containing compounds to ammonia and other potential cerebral toxins. The administration of lactulose to humans causes an increase in fecal nitrogen, but very little increase in ammonia nitrogen. Most of the nitrogen is contained in the fecal bacterial and the soluble fractions of stool. The administration of lactulose causes a reduction in the urea production rate consistent with a reduced entry of ammonia into portal blood, but it does not appear to directly inhibit urea degradation. Other non-absorbable saccharides, particularly those contained in dietary fiber, appear to have effects similar to those of lactulose. There is some evidence that neomycin can be given with lactulose to cause an additive effect in the treatment of hepatic encephalopathy. This effect is most prominent in patients who have not responded adequately to lactulose alone. At this point, the other antibiotics studied do not appear to have additive effects with lactulose.

Lactulose and combination therapy of hepatic encephalopathy: the role of the intestinal microflora.

Lactulose is the most frequently utilized agent in the treatment of hepatic encephalopathy because of its efficacy and the fact that it has few serious side effects. How this nonabsorbable disaccharide works has been a matter of controversy, but evidence suggests that metabolism by the enteric flora is necessary for its mechanism of action. When the intestinal flora metabolized lactulose, bacterial incorporation of nitrogen increases as does the bacterial mass. The presence of a carbohydrate and the acidic environment caused by the production of organic acids also act to reduce the breakdown of other nitrogen-containing compounds to ammonia and other potential cerebral toxins. The administration of lactulose to humans causes an increase in fecal nitrogen, but very little increase in ammonia nitrogen. Most of the nitrogen is contained in the fecal bacterial and the soluble fractions of stool. The administration of lactulose causes a reduction in the urea production rate consistent with a reduced entry of ammonia into portal blood, but it does not appear to directly inhibit urea degradation. Other nonabsorbable saccharides, particularly those contained in dietary fiber, appear to have effects similar to those of lactulose. There is some evidence that neomycin can be given with lactulose to cause an additive effect in the treatment of hepatic encephalopathy. This effect is most prominent in patients who have not responded adequately to lactulose alone. At this point, the other antibiotics studied do not appear to have additive effects with lactulose.

Late hepatic artery thrombosis in liver allograft recipients is associated with intrahepatic biliary necrosis.

Hepatic artery thrombosis (HAT) after liver transplantation is a potentially life-threatening complication that occurs in 2-25% of patients, depending on several risk factors and the patient population studied. Arterial thrombosis occurring early after liver transplantation is associated with acute fulminant hepatic failure, biliary tract necrosis and leaks, or relapsing bacteremia and is associated with a high rate of graft loss and patient mortality. The onset of late posttransplant HAT (after 6 months) has been thought to have a more benign and often asymptomatic course. The reasons for the differences between the manifestations of early and late HAT are not well understood. We reviewed the adult liver transplant experience at the University of Cincinnati and found four patients with late HAT, three of whom developed severe intrahepatic biliary necrosis. Two patients were successfully retransplanted and 1 patient who refused retransplantation died. One patient had mild, transient graft damage due to gradual arterial stenosis and the development of arterial collaterals prior to thrombosis. Late HAT has a significant potential for irreversible graft damage requiring retransplantation. Screening for the development of hepatic artery stenosis prior to late thrombosis may be worthwhile.

Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis.

Cirrhotic patients with hereditary hemochromatosis (HHC) have an increased risk of primary liver cancer (PLC). The purpose of this study was to determine the prevalence of primary liver cancer in patients with HHC undergoing orthotopic liver transplantation (OLT). Five liver transplant centers were surveyed; clinical and pathological data on 37 patients with HHC undergoing OLT were retrospectively collected and analyzed. The diagnosis of HHC was established by a combination of serum transferrin-iron saturation, hepatic iron index (HII), and/or pattern of liver iron staining. The diagnosis of HHC had been unsuspected before OLT in 13 of 37 (35%). Primary liver cancer was found in the explants of 10 of 37 patients (27%) and was unsuspected in 7 of 10 (70%); 8 were hepatocellular carcinoma, and 2 were cholangiocarcinoma; foci of hepatocyte dysplasia were found in 6 additional patients. Mean (+/- SEM) hepatic iron content and HII in 20 patients without prior phlebotomy or bleeding were 17.2 mg/g dry weight (+/- 2.9) and 5.5 (+/- 0.8), respectively. The overall 1-year survival rate after OLT in the 37 HHC patients was 58% (v 55% for HHC patients with PLC). We draw the following conclusions: (1) the diagnosis of HHC is often unsuspected before OLT, and HHC should be evaluated pretransplantation by direct and indirect markers; (2) HHC patients undergoing OLT have a high prevalence of primary liver cancer, the majority being unsuspected; and (3) HHC patients have poorer than average survival after OLT, which cannot be explained solely by the presence of concomitant PLC.

Expression of platelet-derived growth factor in a model of acute liver injury.

Platelet-derived growth factor has been shown to play an important role in the repair process after acute tissue injury and in the pathogenesis of several fibrogenic disorders. The aim of this study was to evaluate whether increased expression of platelet-derived growth factor and its beta-receptor subunit occurs in a model of acute liver injury. Male Sprague-Dawley rats were given a single intragastric dose of carbon tetrachloride and killed at intervals of 24, 48 and 72 hr and 1 wk. Control animals were included in each group. Platelet-derived growth factor-B chain mRNA expression, analyzed by RNase protection assay, was not detectable in control samples or in samples obtained 24 hr or 1 wk after carbon tetrachloride. However, the presence of protected fragments of 130 kb was clearly detected after 48 hr and was still present, although less abundant, after 72 hr. The distribution of platelet-derived growth factor protein in liver tissue sections, evaluated by immunohistochemistry, was restricted to centrilobular veins and portal tracts in normal liver. In carbon tetrachloride-treated rats, prominent staining was observed in areas corresponding to hepatocellular necrosis and inflammatory infiltration. This feature, already present at 24 hr after carbon tetrachloride, became more marked at 48 hr with a gradual resolution after 72 hr. The expression of platelet-derived growth factor-receptor beta-subunit mRNA, evaluated by in situ hybridization, was markedly increased after carbon tetrachloride with a peak at 24 hr and was mainly localized over mesenchymal cells in the hepatic sinusoids.(ABSTRACT TRUNCATED AT 250 WORDS)

Restoration of exocrine pancreatic function following pancreas-liver-kidney transplantation in a cystic fibrosis patient.

Pancreatic transplantation for endocrine replacement is well-established for insulin-dependent diabetes mellitus. Exocrine pancreatic function after pancreas transplantation has been maintained after orthotopic cluster transplants for malignancy, and restoration of adequate exocrine function in a previously deficient patient has been reported in a patient with chronic pancreatitis who developed labile diabetes and steatorrhea after pancreatectomy. We performed a triple organ transplant (pancreas, liver and kidney) in a patient with exocrine pancreatic insufficiency and insulin-dependent diabetes related to cystic fibrosis (CF) after he developed hepatic and renal failure. Pancreatic exocrine secretions were drained enterically to the jejunum. At 24-month follow-up, malabsorption is absent. The 3-day stool fat, stool trypsin and chymotrypsin are normal. Serum carotene is within the normal range. Exocrine pancreatic insufficiency in CF patients can be corrected by pancreas transplantation. However, routine use in CF is precluded by the risks of surgery and immunosuppression. For diabetic patients with pancreatic exocrine insufficiency who require another organ transplant (e.g., lung, liver, or kidney), simultaneous pancreas transplantation with the exocrine secretions directed into the upper gastrointestinal tract should be considered.

Terminal hepatic failure in erythropoietic protoporphyria.

Erythropoietic protoporphyria is an inherited disorder characterized biochemically by a deficiency of ferrochelatase, the enzyme that catalyzes the incorporation of ferrous iron into protoporphyrin to form heme. We describe a patient who illustrates the unpredictability of the course of liver disease in erythropoietic protoporphyria. She remained stable for several years after her first evidence of liver function abnormalities. Then, in a period of weeks, hepatic failure developed and she died. Findings of serial liver biopsy specimens showed extensive hepatocellular degeneration and inflammation that appeared in a 10-day period. The factors that cause this rapid deterioration in hepatic function remain unknown. Reported cases of fatal hepatic failure in patients with erythropoietic protoporphyria are reviewed.

Postsurgical temporomandibular joint hypomobility. Rehabilitation technique.

Specific techniques to treat temboromandibular joint (TMJ) hypomobility caused by capsular restriction are explained. Initially inflammation must be controlled. TMJ manipulation by condylar distraction during opening, protrusion, and lateral movements, and a simple stretching exercise to maintain increased mandibular range of motion, are described. Resistive opening and closing exercises at full opening to relax the lateral pterygoid muscles are prescribed. For all exercises five repetitions, repeated five times per day, are prescribed. These techniques are demonstrated in the successful treatment of a child with a presurgically and postsurgically hypomobile right TMJ.

Orthotopic liver transplantation in two adults with Niemann-Pick and Gaucher's diseases: implications for the treatment of inherited metabolic disease.

Two adults were seen with cirrhosis caused by different lipid storage diseases. A 42-yr-old woman with Niemann-Pick disease type B had marked hepatomegaly, ascites and recent variceal bleeding. Her evaluation showed chronic bilateral pulmonary infiltrates, multiple stigmata of chronic liver disease including the recent cessation of menses, diuretic-resistant sterile ascites, hepatic encephalopathy and variceal bleeding. Five percent of normal sphingomyelinase activity was measured in peripheral leukocytes. A 42-yr-old man with Gaucher's disease and a history of bilateral hip replacements presented with hepatomegaly, jaundice, refractory ascites and renal insufficiency. His evaluation showed 20% to 23% of normal glucocerebrosidase activity in peripheral leukocytes. Both patients underwent orthotopic liver transplantation with resolution of all aspects of decompensated liver function. Assessment of the underlying metabolic defect before and 6 to 14 mo after transplantation showed that after transplantation the patient with Niemann-Pick disease had above normal hepatic sphingomyelinase activity, a less-marked increase in peripheral leukocyte enzyme activity and lower than normal hepatic sphingomyelin and cholesterol content. In contrast, the patient with Gaucher's disease had only a 61% increase in hepatic glucocerebrosidase activity but had an elevated hepatic glucocerebroside content that was only 15% of the pretransplant level and decreased peripheral leukocyte enzyme levels. These findings suggest that variable relationships may exist between posttransplant hepatic and peripheral leukocyte enzyme activities in the different lipidoses, which may have implications for recurrence of glycolipid-induced liver damage.

Increased muscle protein catabolism caused by carbon tetrachloride hepatic injury in rats.

This study was undertaken to determine the pathogenesis of muscle atrophy that frequently accompanies liver disease. Hepatic injury was induced in rats by giving weekly intragastric doses of carbon tetrachloride (CCl4) in combination with phenobarbital in the drinking water. Muscle protein catabolism was assessed during three stages of liver injury and compared with pair-fed controls: group A had hepatic necrosis and inflammation without significant fibrosis; group B had cirrhosis as well as necrosis and inflammation; and group C had cirrhosis with minimal necrosis and inflammation. In group A, vastus lateralis white muscle, which contained predominantly fast glycolytic fibers, showed a significant increase in protein catabolic rates compared with pair fed controls (0.95 +/- 0.05 nmol tyrosine released.mg-1.2 h-1 vs. 0.86 +/- 0.04; P less than 0.05). In group B, protein catabolic rates were significantly increased in vastus lateralis white muscles, as well as two muscles that have a mixed fiber composition, diaphragm, and triceps. Protein catabolic rates were not increased in soleus muscle that predominantly contained slow oxidative fibers in either group A or B. In group C rats there was no increase in catabolic rates in diaphragm or vastus lateralis white muscle. None of the muscles from group B had any impairment in protein synthesis. In diaphragms from group B animals, there was a selective reduction in the cross-sectional areas of fast glycolytic fibers (3725 +/- 224 mm2 control vs. 2926 +/- 208 mm2 experimental; P less than 0.01). This study indicated that liver injury characterized by inflammation and hepatocyte necrosis, with or without cirrhosis, was associated with muscle atrophy that selectively affected fast glycolytic fibers. This muscle atrophy was caused by an increase in protein catabolism and was not the result of an inhibition of protein synthesis.

Decreased hepatic glycogen content and accelerated response to starvation in rats with carbon tetrachloride-induced cirrhosis.

Glucose homeostasis and fatty acid metabolism are abnormal in patients with cirrhosis. To assess the metabolic response to starvation in an animal model of cirrhosis, glycogen and fuel metabolism were characterized in rats with CCl4-induced cirrhosis studied 2 wk after 10 weekly doses of CCl4. Plasma concentrations of glucose and beta-hydroxybutyrate were not different between fed CCl4-treated and control rats, but plasma nonesterified fatty acid concentrations were higher in cirrhotic animals (0.25 +/- 0.01 vs. 0.39 +/- 0.04 mmol/L; p less than 0.05). After 12 hr of starvation, the plasma nonesterified fatty acid concentration had reached 0.58 +/- 0.04 mmol/L in CCl4-treated rats, compared with 0.38 +/- 0.04 mmol/L in control rats (p less than 0.05). The redistribution of the hepatic carnitine pool toward acylcarnitines, which is characteristic of starvation, was complete after fasting for 12 hr in the CCl4-treated rats, compared with the 24 hr required in control rats. In fed cirrhotic rats, liver glycogen content per gram liver was decreased by 64% compared with control rats (30.0 +/- 5.1 vs. 10.8 +/- 1.1 mg/gm liver wet wt; p less than 0.05). After 12-hr fasting, hepatic glycogen content had fallen to 14.3 +/- 3.9 and 4.8 +/- 0.4 mg/gm liver wet wt (p less than 0.05) in control and cirrhotic animals, respectively. To further characterize the status of glycogen metabolism in cirrhotic livers, activities of glycogen synthase and glycogen phosphorylase were determined. Hepatic active and total glycogen phosphorylase activities normalized to hepatocellular content were unaffected by CCl4 treatment, whereas total glycogen synthase activity was increased by 45%.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of branched-chain amino acids on nitrogen metabolism in patients with cirrhosis.

This study was conducted to determine whether an amino acid solution enriched with branched-chain amino acids altered protein catabolic rates and plasma ammonia in patients with cirrhosis. Nine stable subjects were given two peripheral intravenous infusions: a standard amino acid solution (solution A) and a branched-chain-enriched solution containing 97% more leucine (solution B). Each solution was given for separate 9-day (group 1, n = 6) or 3-day (group 2, n = 3) periods. Amino acid solutions delivered 0.7 gm protein.kg-1.day-1. Diets provided an additional 0.3 gm protein plus maintenance calories. Protein turnover was assessed by a primed continuous infusion of [1-14C] leucine in six patients (three patients in group 1 and three patients in group 2). Nitrogen balance and urinary 3-methyl histidine excretion were determined in group 1 patients. Compared with solution A, solution B increased leucine flux and leucine oxidation but had no significant effect on protein synthesis or catabolism based on the plasma specific activity of either leucine or alpha-ketoisocaproic acid. The additional leucine infused with solution B was quantitatively oxidized. Nitrogen balance did not differ with the two solutions and there was also no difference in the urinary excretion of 3-methyl histidine, suggesting that muscle protein catabolism was unchanged. Plasma ammonia concentration decreased significantly during the infusion of solution B and was associated with a slight fall in plasma glucagon concentration. The results indicated that a branched-chain-enriched amino acid solution did not alter protein synthesis or catabolism although it did lower the plasma ammonia when compared with a standard amino acid formula in stable cirrhotic patients.

Stimulation of jejunal mucosal protein synthesis by luminal glucose. Effects with luminal and vascular leucine in fed and fasted rats.

This study was conducted to determine whether short-term (1.75 h) luminal glucose perfusion increases the mucosal protein synthesis rate in rat small intestine. A luminal perfusate containing 56 mM glucose was compared with a control perfusate containing mannitol in two jejunal segments constructed in the same animal. Mucosal protein synthesis rates were determined when the tracer amino acid was administered intravenously and intraluminally. The results indicated that luminal glucose perfusion rapidly stimulated mucosal protein synthesis in the fed state by 20% and 37% with the labeled amino acid derived from the vascular and luminal compartment, respectively. A 16-h fast abolished the stimulatory effect of glucose when the labeled amino acid was given intravascularly but not intraluminally. These effects of glucose could be ascribed to a direct alteration of mucosal metabolism rather than to indirect systemic effects.