A pilot study on the hemodynamic effect of short-term ursodeoxycholic acid therapy in patients with stable liver cirrhosis.

OBJECTIVE: Total serum bile acid concentrations are elevated in individuals with liver disease. Ursodeoxycholic acid (UDCA) therapy in such patients results in a further significant rise in plasma levels to the extent that it becomes the major circulating bile acid. In laboratory animals, bile acids, such as taurocholic acid, have also been shown to possess a diuretic-like action, as they can promote diuresis, natriuresis, and kaliuresis by inhibiting tubular sodium reabsorption. The aim of the present study was to assess the effect of 1 month's UDCA therapy on cardiovascular function in cirrhotic patients. METHODS: Two groups of patients with cirrhosis were studied, six with primary biliary cirrhosis (PBC) and six with postnecrotic liver cirrhosis (PNC). Cardiovascular function was assessed by determination of blood pressure, heart rate, and by two-dimensional and pulsed Doppler echocardiography. RESULTS: In PBC patients, 1 month's treatment with UDCA significantly reduced diastolic volume without changing systolic, diastolic, and mean blood pressures, heart rate, systolic and stroke volumes, ejection fraction, cardiac output, and systemic vascular resistance. In PNC patients, UDCA significantly reduced cardiac output, with a tendency to reduce left ventricular volumes, without any changes in systolic, diastolic, and mean blood pressures. CONCLUSIONS: UDCA caused reductions in diastolic volume in the PBC patients and cardiac output in the PNC patients. Such reductions are not unlike that seen in individuals treated with diuretics. This diuretic-like action deserves further study, particularly in cirrhotic patients who are also being treated with diuretics or show evidence of cardiac myopathy.

Low-dose vasopressin restores diuresis both in patients with hepatorenal syndrome and in anuric patients with end-stage heart failure.

OBJECTIVES: The purpose of this study was to confirm earlier reports that low-dose vasopressin (LDVP) analogues promote urine output in patients with hepatorenal syndrome (HRS) and to check whether this mode of therapy could also be effective in renal shutdown due to nonhepatic conditions. DESIGN: A prospective, open, interventional study. SETTING: An intermediate-level (step-down) medical intensive care unit within a general medical ward of a large university-affiliated hospital. SUBJECTS: Eighteen successive hospitalized patients with HRS (mean age 65 +/- 13 years) and 11 patients with end-stage congestive heart failure (CHF) (mean age 81 +/- 5 years) who failed to restore urine output with conventional treatment (fluids, dopamine, and diuretics) given for at least 24 h. INTERVENTIONS: The patients received LDVP (1 IU h-1) continuously in addition to the conventional treatment. MAIN OUTCOME MEASURES: Urine output and creatinine clearance every 24 h. RESULTS: In the HRS group, before treatment the urine output was 155 +/- 9 mL 24 -1h (mean +/- SD). After treatment with LDVP for 24, 48, and 72 h, urine output improved to 1067 +/- 87, 1020 +/- 501, and 1311 +/- 988 mL 24 -1h, respectively (P < 0.0001 for all measures; two-tailed paired t-test). In the CHF group, before treatment the urine output was 99 +/- 99 mL 24 -1h. After treatment with LDVP for 24, 48, and 72 h, this improved to 1125 +/- 994 mL 24 -1h (P = 0.0028), 1821 +/- 1300 mL 24 -1h (P = 0.004), and 2920 +/- 2423 mL 24 -1h (P = 0.0012), respectively. The improvement in urine output was not accompanied by a parallel improvement in creatinine clearance. The overall outcome did not change, and all patients except two in each group succumbed to their end-stage disease, due to nonrenal causes. CONCLUSIONS: LDVP is effective in restoring urine output both in HRS and in CHF. This suggests that LDVP affects mechanisms not specifically related to liver disease. LDVP may be useful in critical patients with renal shutdown whilst awaiting liver or heart transplantation.

Effect of vascular endothelial growth factor on hepatic regenerative activity following partial hepatectomy in rats.

BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) is an angiogenic factor with a growth-promoting effect that is thought to be restricted to vascular endothelial cells. Its essential role during liver regeneration has yet to be determined. The aim of this study was to document the effect of exogenous VEGF administration on liver regeneration in rats undergoing submaximal hepatic resections. METHODS: Adult male Sprague-Dawley rats (n = 4/group) undergoing 30% partial hepatectomy were administered 200 ng VEGF165 intravenously and were sacrificed at 24, 36, and 48 h postoperatively. Liver regeneration was monitored by measuring the restituted liver mass, proliferating cell nuclear antigen (PCNA) immunostaining, and hepatic PCNA protein by Western blot. RESULTS: Changes in restituted liver mass 48 h postsurgery were more prominent, but did not differ statistically between VEGF-treated and control rats (47% vs. 29%; p<0.06). Nevertheless, PCNA immunostaining showed increased labeling index of hepatocytes, apparent at 36 and 48 h after partial hepatectomy (38% vs. 18% [p<0.041 and 42% vs. 11% [p<0.021], respectively). Hepatic PCNA proteins measured by Western blot showed a 3-fold increase in VEGF-treated rats 48 h postsurgery compared with controls (p<0.01). CONCLUSION: Exogenous VEGF administration early after partial hepatectomy stimulates liver regeneration in rats. Whether or not VEGF165 is a direct mitogen for hepatocytes remains to be determined.

[Superficial skin necrosis--an uncommon manifestation of short bowel syndrome].

Short bowel syndrome causes a complex of symptoms due to compromise of small intestinal nutrient absorption. A 60-year-old woman underwent major resection of the small intestine due to a road accident 3 years ago. The sole manifestation of short-bowel-syndrome was superficial skin necrosis due to vitamin K deficiency. She was asymptomatic for a long time, until treatment with antibiotics further intensified initially subclinical malabsorption. It is not clear why there had been no other symptoms and why the main impact was on the fibrinolytic system rather than the coagulation system, as is usually the case. It is recommended that patients after major resection of the small intestine be closely monitored for coagulation function if an oral antibiotic is prescribed.

Nitric oxide inhalation for paraquat-induced lung injury.

BACKGROUND: When ingested, concentrated paraquat can cause either rapid death from multisystem failure and cardiovascular shock or delayed death from progressive pulmonary fibrosis. Diquat ingestion does not usually cause pulmonary fibrosis, but produces early onset acute renal failure. CASE REPORT: A 52-year-old male ingested approximately 50 mL of a solution containing 13% paraquat and 7% diquat (about 6650 mg of paraquat and 3500 mg of diquat), and subsequently developed adult respiratory distress syndrome and pulmonary fibrosis. Survival prediction employing the criteria of Hart et al. for paraquat plasma levels was 30%. From the probable amount of paraquat ingested, severe toxicity was expected. The clinical course was not consistent with significant diquat toxicity. Treatment included oral Fuller's earth, forced diuresis, hemofiltration, N-acetylcysteine, methylprednisolone, cyclophosphamide, vitamin E, colchicine, and delayed continuous nitric oxide inhalation. The patient recovered and pulmonary function was subsequently normal. CONCLUSION: It is unclear which, if any, of the above treatments contributed to recovery, but the encouraging outcome suggests a possible benefit of nitric oxide inhalation in paraquat poisoning which deserves further study.

Prognostic value of generation of growth hormone-stimulated insulin-like growth factor-I (IGF-I) and its binding protein-3 in patients with compensated and decompensated liver cirrhosis.

Our aim was to study the prognostic value of growth hormone (GH) -stimulated insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) generation in patients with compensated [group 1 (N = 8) with a Child-Pugh (CP) score of 5-8] and decompensated postnecrotic liver cirrhosis [group 2 (N = 7) with a CP score of 9-12]. Serum levels of IGF-I, GH-binding protein (GHBP), and IGFBP-3 were measured before and 24 hr after a single subcutaneous injection of recombinant human GH (rhGH, 0.14 units/kg). Patients (mean age 56 years) were followed prospectively for three years. Six patients (40%) died during the follow-up period, of whom half had a CP score <9. Mean serum IGF-I levels 24 hr after rhGH injection (group 1 vs group 2, 17.4 +/- 6.8 vs 7.4 +/- 0.7 nmol/liter) predicted survival with 93% accuracy. Levels <10 nmol/liter portended a poor prognosis, with 15% survival at one year, whereas levels >10 nmol/liter had a 100% survival rate at one and two years, respectively. Baseline IGF-I (9.98 +/- 2.0 vs 6.38 +/- 0.8 nmol/liter), GHBP (9.2 +/- 3 vs 5.7 +/- 0.8%/50 microl), and IGFBP-3 serum levels at baseline (1.7 +/- 0.3 vs 0.86 +/- 0.2 mg/liter) and at 24 hr (2.04 +/- 0.38 vs 0.99 +/- 0.3 mg/liter) did not add to the predictive value of stimulated IGF-I levels at 24 hr and were less accurate in predicting the outcome in comparison to CP score (80%). We conclude that stimulated IGF-1 <10 nmol/liter may be a true predictor of a negative prognosis in patients with liver cirrhosis.

Growth hormone-stimulated insulin-like growth factor (IGF) I and IGF-binding protein-3 in liver cirrhosis.

BACKGROUND/AIMS: The aim of this study was to evaluate the liver's potential to generate insulin-like growth factor (IGF) I and IGF-binding protein-3 (IGFBP-3), following stimulation by human recombinant growth hormone, as a possible marker for liver functional reserve in patients with liver cirrhosis. METHODS: In a pilot study, 15 patients (mean age 56 years) with postnecrotic liver cirrhosis were divided into two groups according to disease severity (Child-Pugh score): Group 1 (n=8) with scores of 5-8 and Group 2 (n=7) with scores of 9-12. Five age-matched healthy subjects served as controls. Human recombinant growth hormone (0.06 mg/kg) was administered subcutaneously on 2 consecutive days. Serum levels of IGF-I and IGFBP-3 were measured before and up to 48 h after human recombinant growth hormone injection. Nutritional status was assessed by the creatinine-height index and was compared to lymphocyte count, body mass index, and muscle arm circumference. RESULTS: Baseline IGF-I levels were significantly lower in patients with cirrhosis than in controls, while no differences were noted between the two patient groups. IGF-I levels increased significantly after rhGH administration to the healthy controls, to a lower degree in Group 1, while no change occurred in Group 2. IGF-I levels at 24 h and beyond correlated significantly with the nutritional status, the Child-Pugh score, and the basal levels of GH-binding protein and IGFBP-3. IGFBP-3 serum levels did not change after rhGH stimulation. CONCLUSIONS: IGF-I generation after GH stimulation may provide a new dimension in the assessment of liver function and nutritional status in patients with liver cirrhosis.

Basic fibroblast growth factor is hepatotropic for rat liver in regeneration.

A role for fibroblast growth factor in liver regeneration has recently been suggested. In this study we followed the intravenous delivery of recombinant human [125I]basic fibroblast growth factor to the liver of rats following 68% partial hepatectomy. The concentration of [125I]basic fibroblast growth factor was higher in the liver (mean +/- SD, 6.8 +/- 0.89% of injected dose) and the kidney (6.7 +/- 0.2%) of sham-operated rats than in the spleen (2.8 +/- 0.45%). It increased threefold in the liver only, soon after 68% partial hepatectomy (20.3 +/- 5.3%, p < 0.001), and remained high for the first 24 h. We also studied the effect of basic fibroblast growth factor injection on the rate of [3H]thymidine incorporation into liver DNA in rats subjected to either 21% or 68% partial hepatectomy. A significant increase was seen after intramesenteric injection of 500 ng basic fibroblast growth factor into rats subjected to 21% partial hepatectomy (23.5 +/- 7.3 cpm/micrograms DNA) compared to saline-injected rats (14.5 +/- 6.4 cpm/micrograms DNA, p = 0.034). A dose of 5000-25,000 ng injected into a peripheral vein resulted in higher thymidine incorporation than in saline-injected control rats (36.9 +/- 12.7 and 9.7 +/- 6.1 cpm/micrograms DNA, respectively; p < 0.0001). No significant effect was seen after 68% partial hepatectomy. Autoradiography showed that the hepatocytes were the predominant labelled cells early after hepatectomy and basic fibroblast growth factor injection. We conclude that basic fibroblast growth factor uptake by the liver is increased after 68% partial hepatectomy and that basic fibroblast growth factor is mitogenic to liver parenchymal cells early after 21% partial hepatectomy.

HLA-DR positive epidermal Langerhans' cells in liver cirrhosis and immunosuppressed liver transplanted patients.

The aim of the present study was to evaluate the number of Langerhans' cells (LC) in immunosuppressed liver transplanted patients, compared to patients with liver cirrhosis and healthy volunteers. The detection of LC was performed in the epidermal sheet of each patient by using indirect immunoperoxidase and ATPase staining. A significant reduction in the number of LC was found in the liver transplanted patients as compared to patients with liver cirrhosis and healthy volunteers. This reduction may be related to prolonged treatment with corticosteroids and azathioprine.

[Transjugular liver biopsy in patients with bleeding tendency].

Transjugular liver biopsy (TJB) was successful in 14 of 23 patients with chronic liver disease and abnormal coagulation profiles. There were 7 men and 7 women between the ages of 20 and 65. No bleeding followed the procedure, nor were there any other significant complications. The size of the specimens and the number of portal spaces included were compared with those obtained by percutaneous liver biopsy from 12 patients with advanced liver cirrhosis. TJB samples were smaller than those obtained by percutaneous biopsy (0.56 +/- 1.6 cm vs 1.0 +/- 0.05) and contained fewer portal spaces (2.2 +/- 1.6 vs 3.4 +/- 2.3). Despite the smaller size, the contribution of TJB to diagnosis and prognosis was defined as good in 78% of the patients. We conclude that TJB is safe and is an important tool for liver tissue diagnosis in patients with bleeding tendency.

Pregnancy after liver transplantation.

Two patients who became pregnant after liver transplantation for end-stage liver disease were carefully monitored using pulsed Doppler waveform measurements. One patient with Wilson's disease, on triple immunosuppressive therapy including prednisone, azathioprine and low-dose cyclosporin A, delivered a healthy girl weighing 2650 g after 38 weeks' gestation. The other patient, with HBV-related postnecrotic cirrhosis, became pregnant less than 3 months postoperatively, under triple therapy, after being amenorrheic for 6 years. Episodes of elevation in liver enzymes were noted, and severe osteoporosis with low back pain developed. A healthy boy weighing 2975 g was born at 35 weeks' gestation. Our cases add to previous reports of successful pregnancies under cyclosporin A immunosuppression.

Growth hormone-binding protein in partially hepatectomized rats.

The role of the liver in regulating serum growth hormone-binding protein (GH-BP) was studied. We measured rat serum GH-BP and insulin-like growth factor 1 (IGF-1) 30 min to 96 h after 70% partial hepatectomy (PHP) or sham operation in adult male rats. Serum GH-BP declined sharply from 5.8 +/- 0.1% at baseline to 3.9 +/- 0.5% by 48 h following PHP. By 72 h serum GH-BP at baseline to 3.9 +/- 0.5% by 48 h following PHP. By 72 h serum GH-BP returned to baseline level and remained at that level 96 h postoperatively. In sham-operated female rats, serum GH-BP was about 2-fold higher than in males (10.5 +/- 1.46 versus 5.8 +/- 0.2%), whereas 24 h after hepatectomy a significant drop of about 50% was observed (p < 0.001). Serum IGF-1 decreased within 2-4 h postoperatively in both sham-operated and PHP groups, but thereafter was lower in the PHP rats, up to 48 h after operation, compared to sham-operated rats (p < 0.03). The study shows that the liver has an important role in the determination of serum GH-BP levels. The return to normal GH-BP level, even before the liver regained its full size following hepatectomy, suggests an increase in GH-BP production by the regenerating liver.

Anamnestic response to hepatitis B vaccine in nonalcoholic liver cirrhosis patients with and without HBV-DNA.

Two methods were used to unveil a possible previous hepatitis B virus (HBV) infection in patients with postnecrotic liver cirrhosis. The anamnestic response to a booster injection of HB vaccine was assessed, and the polymerase chain reaction (PCR) technique for the detection of HBV-DNA in serum and liver tissue, using primers to span the precore and core regions, was employed. Seventeen patients with postnecrotic liver cirrhosis were selected from a population with a high prevalence of HBV infection and were compared with 11 liver cirrhosis patients who were positive for antibodies to surface antigen (anti-HBs) IgG antibodies. All patients were given one dose of HB vaccine into the deltoid muscle, and anti-HBs titers were measured 1 and 4 wk after injection. Three of 17 patients, initially negative for anti-HBs, showed a primary response, with titers of anti-HBs rising from 0 to a maximum of 85 mIU/ml after 4 wk; the rest had no response. Of the 11 patients positive for anti-HBs, of whom nine were also IgG anti-HBs positive, only four had an intense anamnestic response, with anti-HBs titers rising to more than 10 times the initial values (up to 10,800 mIU/ml). Serum HBV-DNA was detected in eight patients in the antibody-negative group and in only one patient in the antibody-positive group (p less than 0.02). None of the four patients with positive anamnestic response had HBV-DNA in the serum. The prevalence of HBV-DNA in the liver was similar in both groups. Absence of HBV-DNA in serum of most patients positive for anti-HBs supports the hypothesis that HBV particles released from the liver may be captured by antibodies in the serum. We conclude that assessment of the anamnestic response to HB vaccine has no diagnostic advantage, compared with direct measurement of conventional HBV serological markers in patients with liver cirrhosis. Moreover, we suggest that this type of immunologic response may not occur when virion-associated HBV-DNA is present in the serum.

Gonadotropin-releasing hormone analogues for dysfunctional bleeding in women after liver transplantation: a new application.

A new clinical indication for GnRH agonists treatment seems to exist in addition to the many indications known so far (4, 5). These previously mentioned indications include: uterine fibroids, precocious puberty, endometriosis, polycystic ovarian disease, ovulation induction for assisted fertilization (in vitro or in vivo), treatment of various tumors such as prostatic, breast, pancreatic, ovarian, and pituitary tumors, and various catamenial disorders such as premenstrual syndrome and porphyria. Women after liver transplantation, who are in the reproductive age and who experience menometrorrhagia or dysfunctional bleeding, seem to be a new indication for application of these useful GnRH analogues. This application may prevent the potential hepatotoxicity or cholestasis of E-P combinations usually used for treatment of dysfunctional bleeding. The recommended treatment is of relatively short duration (3 to 6 months), within the first 2 years of the transplantation, after which a more prolonged treatment should be considered. This treatment may also spare the need for contraception during its administration because both oral contraceptives and intrauterine device are relatively contraindicated in these patients (the latter because of the immunocompromised state). We believe this application to become more common because of increasing numbers of liver transplantations and improved survival rate. It may be looked at as a "new application of a relatively new drug for a new and enlarging situation."