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Biomedical subjects

M R Charlton

Publications and source records attributed to M R Charlton.

At least 19 recordsLinked to original sources
PubMed2001

Recurrent autoimmune hepatitis after orthotopic liver transplantation.

To determine the frequency, risk factors, and consequences of recurrent autoimmune hepatitis after liver transplantation, 41 patients with type 1 disease were monitored after surgery in accordance with a surveillance protocol. Tacrolimus or cyclosporine plus prednisone were administered to each patient, and liver biopsy examinations were performed at least annually according to protocol. Corticosteroid therapy was ultimately discontinued in only 2 patients. Recurrent disease was defined as the presence of lymphoplasmacytic infiltrates in liver tissue in the absence of other causes of allograft dysfunction. Autoimmune hepatitis recurred in 7 patients (17%), and the mean time to recurrence was 4.6 +/- 1 years. Recurrence was asymptomatic in 4 of 7 patients and detected only by surveillance liver biopsy assessment in 2 patients. Histological changes were mild, and there was no progression to cirrhosis during 4.9 +/- 0.9 years of observation. Five-year patient (86% v. 82%; P =.9) and graft (86% v. 67%; P =.5) survival rates were not statistically different between patients with and without recurrent disease. HLA-DR3 or HLA-DR4 occurred more commonly in patients with than without recurrence (100% v. 40%; P =.008) and healthy subjects (100% v. 49%; P =.01). Recurrent disease was unrelated to donor HLA status. In conclusion, recurrence after transplantation for type 1 autoimmune hepatitis is common. Its mild manifestations and favorable prognosis may reflect early detection by a surveillance protocol and/or continuous corticosteroid treatment. HLA-DR3- or HLA-DR4-positive recipients are at risk for recurrence regardless of donor HLA status.

Adult↗
PubMed2000

Comparative allograft histology after liver transplantation for cryptogenic cirrhosis, alcohol, hepatitis C, and cholestatic liver diseases.

BACKGROUND: End-stage liver disease for which no cause can be identified, cryptogenic cirrhosis, is a common indication for liver transplantation. Allograft inflammation and fibrosis have been reported to recur with similar frequencies after liver transplantation for cryptogenic cirrhosis and hepatitis C (HCV). METHODS: We determined sequential posttransplant allograft histology in four groups of recipients: 31 transplanted for cryptogenic cirrhosis, 70 for cholestatic etiologies, 40 for alcoholic liver disease, and 56 for HCV. Modified hepatitis activity index (HAI) and fibrosis stage were determined at 4 months, 1 year, and at most recent biopsy posttransplantation. RESULTS: The prevalence of HAI > or = 2 among cryptogenic recipients was similar to that of cholestatic and alcoholic recipients at 4 months, 1 year, and at most recent evaluation (mean 45+/-17 months posttransplantation). For HCV-infected recipients, the frequency of HAI > or = 2 was more than for cryptogenic recipients at 1 year (52 vs. 29%, P=0.04) and at most recent evaluation (64 vs. 15%, P=0.003). Fibrosis scores for cryptogenic, cholestatic, and alcoholic recipients were similar at all timepoints. The proportion of HCV-infected recipients with fibrosis stage >2 was more than that of cryptogenic recipients at 4 months (29 vs. 12%, P=0.05), 1 years (46 vs. 7%, P=0.0002), and at most recent evaluation (42 vs. 15%, P=0.06). None of the cryptogenic recipients developed cirrhosis. RESULTS: The frequency of elevated HAI and fibrosis stage in recipients who undergo transplantation for cryptogenic cirrhosis is similar to that of recipients who undergo transplantation for cholestatic etiologies and significantly less than that of HCV-infected recipients. Fibrosis stage and HAI are generally stable after transplantation for cryptogenic cirrhosis. These data do not suggest a viral etiology of liver disease in the majority of patients with cryptogenic cirrhosis.

Biopsy↗
PubMed2000

Early detection of hepatitis C allograft reinfection after orthotopic liver transplantation: a molecular and histologic study.

After orthotopic liver transplantation (OLT), patients with chronic hepatitis C virus (HCV) infection show nearly universal persistence of viremia and reinfection of the liver, but identifying the point at which the liver is reinfected morphologically can be difficult. One tool that may potentially be useful to detect reinfection is reverse transcriptase-polymerase chain reaction (RT-PCR), which has proven to be highly sensitive for detecting HCV RNA in formalin-fixed paraffin-embedded liver tissue. Our purpose was to gain insight into the time frame of HCV reinfection by assaying for HCV RNA in serial posttransplant liver biopsy specimens. Our study population consisted of 14 patients who underwent liver transplantation for hepatitis C and had confirmed HCV RNA in pretransplant serum, absence of HCV RNA in donor livers, and available consecutive posttransplant liver allograft specimens. We performed RT-PCR for HCV RNA in serial posttransplant liver biopsy specimens, beginning at 1 week until at least one biopsy from each tested positive. HCV RNA was detected in liver tissue by RT-PCR in 1-week post-OLT liver samples in 6 of 14 (42.8%) patients, the earliest being 5 days post-OLT. Eventually, each of the remaining eight samples became RT-PCR positive as well; the first detections occurred in these at 3 weeks (three cases), 4 weeks (three cases), 48 weeks (one case), and 144 weeks (one case). Histologic identification of hepatitis C recurrence was relatively insensitive in relation to these molecular data. These data suggest that (1) HCV RNA reinfection is nearly universal after liver transplantation in patients with chronic hepatitis C infection, (2) molecular reinfection by HCV occurs at a variable interval post-OLT, with the majority of allograft livers reinfected as early as 1 week, and (3) morphologic features of hepatitis C are usually appreciable at the time of "molecular" recurrence.

Hepacivirus↗
PubMed2000

Early identification of recipients with progressive histologic recurrence of hepatitis C after liver transplantation.

Approximately half of patients undergoing liver transplantation (LT) for hepatitis C virus (HCV) develop histologic evidence of recurrence within the first postoperative year. Early identification of recipients at risk for more severe recurrence of HCV may be useful in selecting patients for antiviral therapy. We determined whether recipients at greatest risk for more severe recurrence of HCV can be identified by pre- and/or early post-LT HCV-RNA levels in serum or tissue. Serum and tissue samples were prospectively collected pre-LT and at 7 days, 4 months, 1 year, and at 3 years posttransplantation from patients undergoing LT for HCV. Hepatitis activity index (HAI) and fibrosis stage (FS) were assessed in all liver biopsies. Forty-seven patients (32 men) were studied. Higher HCV-RNA levels at 4 months post-LT (>/=10(9) copies/mL, n = 29) were associated with higher HAI at 1 year and at 3 years post-LT. The HAI seen on protocol biopsies at 4 months correlated significantly with fibrosis stage (FS) at 1 year (r =.56, P </=.001) and 3 years (r =. 53, P =.002). Higher HCV-RNA levels at 7 days and 4 months post-LT were sensitive (66% and 84%, respectively) and specific (92% and 63%, respectively) in identifying recipients with an HAI greater than 3 at 3 years. Higher pre- and early post-LT HCV-RNA levels are associated with more severe recurrence of HCV. The correlation of early HAI with subsequent FS suggests that higher mean HAI will eventually translate into more advanced stages of fibrosis. Patients at risk for more severe post-LT recurrence of HCV can be identified by early posttransplant HCV-RNA levels.

Acute Disease↗
PubMed2000

Utility of standard nutritional parameters in detecting body cell mass depletion in patients with end-stage liver disease.

Protein-calorie malnutrition, best measured by body cell mass (BCM) depletion, has been associated with adverse outcomes in patients with end-stage liver disease. We prospectively measured BCM and multiple standard nutritional parameters in patients with end-stage liver disease to determine which, if any, of the traditionally measured nutritional parameters correlate with BCM. A detailed nutritional assessment, including BCM analysis, subjective global assessment, anthropometry, handgrip dynamometry, laboratory tests, and body composition measured by dual-energy X-ray absorptiometry was performed in 69 sequential patients awaiting liver transplantation. The frequency of abnormalities of specific parameters of nutritional status varied between 19% and 99%. Most of the commonly measured parameters of nutritional status correlated poorly with BCM. Patients with depleted BCM (lowest quartile for sex) had midarm circumference (P <.01), arm-muscle circumference (P <.001), handgrip strength (P <.001), blood urea nitrogen (P <.01), and creatinine (P <.01) values less than those for patients with greater BCM (highest 3 quartiles for sex). In multivariate analysis, arm-muscle circumference and handgrip strength were the best predictors of BCM. The combined criteria of handgrip strength less than 30 kg and arm-muscle circumference less than 23 cm have a sensitivity of 94% and a negative predictive value of 97% in identifying patients with depleted BCM. Although abnormalities of nutritional parameters are highly prevalent among patients with end-stage liver disease, most parameters of nutritional status do not correlate with BCM. In patients with end-stage liver disease, arm-muscle circumference and handgrip strength are the most sensitive markers of BCM depletion.

Absorptiometry, Photon↗
PubMed2000

Prevalence of TT virus infection in blood donors with elevated ALT in the absence of known hepatitis markers.

OBJECTIVE: Recently a novel DNA virus (TT virus) has been identified in Japan and shown to be associated with elevated aminotransferase levels after blood transfusion. The exact role of TTV in the pathogenesis of liver disease is yet to be established. Our aim was to determine the prevalence and role of TTV in the pathogenesis of elevated transaminases in healthy blood donors in the absence of markers for viral hepatitis A-C. METHODS: Stored sera were collected from 99 healthy blood donors with elevated alanine amino transferase (ALT) values that were discovered at the time of blood donation. A total of 146 samples were obtained from healthy donors with normal ALT values who were used as controls. None of the patients or controls had a history of blood transfusion or had clinical signs of acute or chronic hepatitis. Serological markers for hepatitis A, hepatitis B, and hepatitis C viruses were negative. TTV DNA was amplified and detected using polymerase chain reaction followed by gel electrophoresis. RESULTS: Five of 99 (5%) samples obtained from donors with elevated ALT had TTV DNA detected by PCR, as compared to one of 146 (0.7%) of those with normal ALT (p = 0.006). Among those with elevated ALT, mean ALT values in patients with TTV (296 +/- 305 U/L) were higher than in patients without TTV (95 +/- 37 U/L), but the difference was not statistically significant (p = 0.08). The two samples with highest ALT values (both >450 U/L) were among the five samples with detectable TTV DNA in serum. CONCLUSIONS: Although TTV is not likely to explain the majority of elevated ALT cases in otherwise healthy blood donors, TTV infection may potentially be associated with some cases. Based on these findings, we propose that the role of TTV in the pathogenesis of acute and chronic liver diseases merits further investigation.

Alanine Transaminase↗
PubMed1999

Recurrent and new hepatitis C virus infection after liver transplantation.

Chronic infection with the hepatitis C virus (HCV) is the most common reason for liver transplantation. We examined the results of laboratory tests for HCV on a cohort of patients who received a liver transplant between 1990 and 1994 at three large centers. Seven hundred twenty-two recipients and 604 donors were tested for antibody to HCV (anti-HCV) using a second-generation enzyme-linked immunoassay (EIA-2), followed by recombinant immunoblot (RIBA-2) and HCV RNA confirmation by reverse-transcription polymerase chain reaction (RT-PCR) (with genotyping and viral quantification). Diagnosis of posttransplantation infection required detection of serum HCV RNA that could be genotyped by sequencing or was repeatedly positive despite being unsequenceable. Twenty-five percent of transplantation candidates were seropositive for anti-HCV. Approximately 86% of anti-HCV-positive, 93% of RIBA-positive, and 97% of HCV RNA-positive candidates developed infection after transplantation. Pretransplantation HCV RNA was superior to RIBA-2 for predicting posttransplantation infection. Whereas HCV genotype was identified in nearly all candidates and changed little after transplantation, serum viral levels rose markedly after transplantation. Fifteen donors were either anti-HCV- or HCV RNA-positive. Recipients of grafts from donors with HCV RNA all developed infection, whereas infection was not detected in recipients of grafts from donors with anti-HCV but without detectable HCV RNA. The rate of new infection fell significantly (P =.02) after the introduction of EIA-2 screening of blood. Donor and candidate markers for HCV predict posttransplantation infection.

Cohort Studies↗
PubMed1999

Recurrence of primary sclerosing cholangitis following liver transplantation.

Recurrence of primary sclerosing cholangitis (PSC) following liver transplantation has been suggested; however, it has not been fully defined because of numerous complicating factors and the lack of diagnostic criteria. In the present study, we investigated the recurrence of PSC by developing strict criteria and applying them to a large cohort of PSC patients who underwent liver transplantation. Between March 1985 and June 1996, 150 PSC patients underwent liver transplantation at the Mayo Clinic; mean follow up was 55 months. The incidence of nonanastomotic biliary strictures and hepatic histologic findings suggestive of PSC were compared between patients transplanted for PSC and a non-PSC transplant control group. Our definition of recurrent PSC was based on characteristic cholangiographic and histologic findings that occur in nontransplant PSC patients. By using strict criteria, 30 patients with other known causes of posttransplant nonanastomotic biliary strictures were excluded leaving 120 patients for analysis of recurrence of PSC. We found evidence of PSC recurrence after liver transplantation in 24 patients (20%). Of these, 22 out of 24 patients showed characteristic features of PSC on cholangiography and 11 out of 24 had compatible hepatic histologic abnormalities with a mean time to diagnosis of 360 and 1,350 days, respectively. Both cholangiographic and hepatic histologic findings suggestive of PSC recurrence were seen in nine patients. The higher incidence and later onset of nonanastomotic biliary strictures in patients with PSC compared with a non-PSC control group is supportive of the fact that PSC does recur following liver transplantation. We were unable to identify specific clinical risk factors for recurrent PSC, and the overall patient and graft survival in patients with recurrent PSC was similar to those without evidence of recurrence. Our observations provide convincing evidence that PSC frequently recurs in the hepatic allograft using strict inclusion and exclusion criteria.

Adult↗
PubMed1999

Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.

Liver transplantation is the only effective therapeutic option for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC). In this study, we analyzed a single center's experience with 150 consecutive PSC patients who received 174 liver allografts. Mean follow-up was 55 months. Actuarial patient survival at 1, 2, 5, and 10 years was 93.7%, 92.2%, 86.4%, and 69.8%, respectively, whereas graft survival was 83.4%, 83.4%, 79.0%, and 60. 5%, respectively. The main indication for retransplantation was hepatic artery thrombosis, and the major cause of death was severe infection. Patients with PSC had a higher incidence of acute cellular and chronic ductopenic rejection compared to a non-PSC control group. Chronic ductopenic rejection adversely affected patient and graft survival. Biliary strictures, both anastomotic and nonanastomotic, were frequent and occurred in 16.2% and 27.2% of patients, respectively. The incidence of recurrent PSC was 20%. A negative impact on patient survival was not seen in patients with either postoperative biliary strictures or recurrence of PSC. Six patients (4%) had cholangiocarcinoma and 1 patient died related to recurrence of malignant disease. Seventy-eight percent of PSC patients had associated inflammatory bowel disease, most commonly chronic ulcerative colitis, which did not adversely impact patient outcome posttransplantation. Nine patients required proctocolectomy after liver transplantation; 5 because of intractable symptoms related to inflammatory bowel disease and 4 due to the development of colorectal carcinoma/high-grade dysplasia. Our data show that liver transplantation provides excellent long-term patient and graft survival for patients with end-stage PSC.

Cause of Death↗
PubMed1999

The clinical significance of simultaneous infection with hepatitis G virus in patients with chronic hepatitis C.

OBJECTIVES: Hepatitis G virus (HGV) is a recently discovered member of the flavivirus family that has been associated with acute and chronic hepatitis. HGV infection has been reported to coexist in 10-20% of patients with chronic hepatitis C. The significance of simultaneous infection with HGV and hepatitis C virus (HCV) remains to be clarified, as do the effects on HGV of therapeutic interventions such as interferon treatment or liver transplantation. THE AIMS OF OUR STUDY WERE: 1) to examine the frequency of HGV infection in the settings of liver transplantation and interferon therapy for hepatitis C; and 2) to compare HGV RNA levels before and after liver transplantation or interferon treatment. METHODS: Pre-treatment sera were available in 65 patients with chronic hepatitis C treated with interferon; pretransplant sera were available in 49 patients transplanted for end stage liver disease associated with chronic hepatitis C. Information collected included age, sex, risk factors for hepatitis, concurrent liver disease, patient and allograft survival, biochemical response to interferon, histological activity index, and degree of fibrosis/cirrhosis. HCV genotyping was performed by sequencing the NS-5 region. HGV quantitation was performed using a research-based branched DNA (bDNA) assay with a set of probes directed at the 5' untranslated region. RESULTS: HGV was detected in 10 of 49 patients (20%) before transplant and in 13 of 65 patients (20%) treated with interferon. There was a female predominance among HGV-positive compared with HGV-negative transplant patients (80% vs 20%; p < 0.01), but such a difference was not observed in the interferon-treated group. Hepatic iron concentration was lower in hepatic explants from patients who were HGV-positive than in those who were HGV-negative (318 +/- 145 microg/g dry weight vs 1497 +/- 2202 microg/g dry weight; p = 0.02). HCV exposure after 1980 was more common in the HGV-positive patients than in those who were HGV-negative for the entire study population (10 of 20 [50%] vs 16 of 66 [24%]; p = 0.03), as well as for the nontransplant subgroup (8 of 12 [67%] vs 12 of 39 [31%]; p = 0.03). HGV RNA levels declined at 1 yr after transplant in seven of eight patients. Among nine patients tested during or after interferon treatment, HGV RNA levels declined from pretreatment levels in all and disappeared in three. CONCLUSIONS: Among patients with chronic hepatitis C treated with either interferon or liver transplantation, the frequency of coinfection with HGV is about 20%. HGV may be a more recent virus in the US than HCV. Coinfection with HGV does not appear to affect the likelihood of response to interferon in patients with hepatitis C. Finally, HGV RNA levels appear to decline after both liver transplantation and interferon therapy, suggesting possible suppression by increased HCV replication in the former case, and a possible drug treatment effect in the latter.

Adult↗
PubMed1999

Clinical significance of TT virus infection in patients with chronic hepatitis C.

OBJECTIVE: The TT virus (TTV) is a novel DNA virus that has recently been identified. The clinical significance of TTV infection in patients with chronic hepatitis C has not been determined. The aim of this study was to determine the prevalence and possible role of TTV in a well characterized population with chronic hepatitis C infection. METHODS: Ninety patients with chronic HCV and known time of HCV acquisition were selected from approximately 250 patients followed at our institution. Characteristics including age, sex, histology, and length of disease were recorded. Direct sequencing of the NS5 region was used for HCV genotyping. TTV DNA detection was based on PCR. RESULTS: TTV infection was present in 24 of 90 (27%) HCV patients. Patients were divided into four groups based on stage of disease; chronic hepatitis (CH, 29 patients), compensated cirrhosis (CC, 17 patients), decompensated cirrhosis (DC, 28 patients), and hepatocellular carcinoma (HCC, 16 patients). TTV was present in 2/29 (7%), 2/17 (12%), 11/28 (39%), and 9/16 (56%) in those with CAH, CC, DC, and HCC respectively. TTV was significantly more prevalent among those with advanced disease (DC and HCC) compared to those with stable disease (CH and CC; p = 0.001). Mean age, sex, and the time from exposure to HCV to development of complications were similar in TTV-positive and -negative patients. TTV infection was more common in patients infected with HCV genotype 1b. Univariate analysis showed that length of HCV infection, HCV genotype 1b, and TTV infection were important in predicting the stage of liver disease in HCV patients. However, after adjusting for length of HCV infection, TTV but not HCV genotype was important in predicting the stage of liver disease. CONCLUSIONS: We conclude that 1) TTV infection is common in patients with chronic HCV; 2) TTV infection is more prevalent among patients with advanced HCV-associated liver disease (DC and HCC) than in those with stable disease (CH and CC); and 3) TTV infection is more common in patients with HCV genotype 1b but is independent from genotype in predicting the stage of HCV-associated liver disease.

Base Sequence↗
PubMed1998

Hepatitis G virus infection in patients transplanted for cryptogenic cirrhosis: red flag or red herring?

BACKGROUND: The significance of hepatitis G (HGV) infection in liver transplant recipients is not known. We set out to determine the pre-orthotopic liver transplantation (OLT) prevalence, the pre- and postoperative viral titers of HGV, and the allograft histology in patients infected with HGV who underwent OLT for cryptogenic cirrhosis. METHODS: HGV RNA was measured using a research-based branched DNA assay. The assay used a target-specific probe set that was based on the 5'-untranslated region of the HGV genome. Allograft histology was assessed with protocol liver biopsies in all patients who survived longer than 6 months. RESULTS: The preoperative prevalence of HGV infection in recipients transplanted for cryptogenic cirrhosis was 26%. Thirty-seven percent (12 of 33) of recipients who had serum available in the first postoperative month had HGV infection. Mean HGV RNA levels were 9.8 (+/-4.2) (viral molecular equivalents/ml x 10[6]) before OLT and 37.5 (+/-10.7) at 1 year after OLT. In 4 of the 11 cryptogenic recipients in whom HGV RNA was detectable in the first postoperative month, HGV RNA fell to undetectable levels at the most recent follow-up (mean 70 months). Of the five cryptogenic recipients who continue to have measurable HGV RNA, three have unexplained hepatitis histologically. CONCLUSIONS: These findings suggest the following: 1) The prevalence of HGV infection in patients undergoing OLT for cryptogenic cirrhosis is about 25%. 2) In recipients persistently infected with HGV, mean HGV RNA titers increase after OLT. 3) HGV RNA becomes undetectable in about one third of recipients who had detectable HGV RNA in the first month after OLT. 4) Hepatitis of uncertain etiology occurs in 60% (3 of 5) of persistently HGV-infected cryptogenic recipients.

Adult↗
PubMed1998

Role of hyperglucagonemia in catabolism associated with type 1 diabetes: effects on leucine metabolism and the resting metabolic rate.

The catabolic state of poorly controlled type 1 diabetes has largely been attributed to insulin deficiency. However, the role of hyperglucagonemia, which occurs concomitantly with insulin deficiency, has not been fully investigated. We studied the effects of hyperglucagonemia during insulin deprivation on energy expenditure (using indirect calorimetry) and protein metabolism (using L-[1-(13)C,15N]leucine and L-[1-(13)C]leucine as tracers) in 12 type 1 diabetic subjects. Five protocols were used: insulin treatment, insulin deprivation, insulin deprivation with suppression of endogenous glucagon with somatostatin (SRIH) and growth hormone replacement, insulin deprivation with endogenous glucagon suppression with SRIH (no growth hormone replacement), and insulin deprivation with SRIH and a high level of glucagon replacement (no growth hormone replacement). It was observed that leucine oxidation and the resting metabolic rate (RMR) were significantly lower during insulin treatment and insulin deprivation with concomitant SRIH infusion (lowering glucagon) than during insulin deprivation alone. Replacement of glucagon at a high level during SRIH infusion in the insulin-deprived state increased leucine oxidation and the RMR. Hyperglucagonemia was also associated with a trend for decreased protein synthesis. Hyperglucagonemia did not affect leucine transamination. Insulin replacement decreased leucine flux and oxidation. Leucine oxidation (R2 = 0.79) and the RMR (R2 = 0.81) were seen, by multiple regression analysis, to correlate with glucagon levels and not with other hormones. We conclude that while insulin deficiency increases protein breakdown, hyperglucagonemia is primarily responsible for the increased leucine oxidation and RMR seen during insulin deprivation.

Adult↗
PubMed1997

Liver transplantation for cryptogenic cirrhosis.

End-stage liver disease secondary to cryptogenic cirrhosis is the indication for orthotopic liver transplantation (OLT) in 7% to 14% of recipients. However, there are no reports documenting the outcome of OLT for this indication. The aim of this study was to determine (1) survival and (2) the incidence of histological recurrence of cryptogenic cirrhosis after OLT. Between March 1985 and December 1994, 560 OLTs were performed at our institution. Of these, 39 transplants for cryptogenic cirrhosis were in patients who met the following criteria: antinuclear antibody < 1:40; negative anti-smooth muscle antibody, antimitochondrial antibody, polymerase chain reaction for hepatitis C virus, and hepatitis B surface antigen results; normal ceruloplasmin and alpha-1 antitrypsin phenotype; transferrin saturation < 65%; and liver biopsy specimen not suggestive of hemochromatosis or other known disorders. Histological recurrence was assessed with protocol liver biopsies in all patients who survived longer than 6 months. The mean age of cryptogenic recipients at the time of transplantation was significantly lower (40.6 years; range, 3 to 63 years) than that of noncryptogenic recipients (48.5 years; range, 1-70; P < .03). Median modified Child's-Pugh score was slightly higher for cryptogenic recipients at the time of transplantation (10.0 + 0.08 standard error of mean [SEM]), than for the noncryptogenic recipients (9.0 + 0.03 SEM; P < .02). Actuarial survival was 72% (+ 0.07 SEM) at 1 and 58% (+ 0.08 SEM) at 5 years for cryptogenic recipients compared with 89% at 1 and 80% at 5 years for noncryptogenic recipients. The difference in survival was significant (P < .001) at both 1 and 5 years. Among the 27 cryptogenic recipients surviving more than 6 months (mean follow-up, 5.5 years), 6 have persistent hepatitis histologically without apparent infectious, vascular, biliary, or drug origins. Four patients (15%) had chronic active hepatitis, and 2 (7%) had steatohepatitis. No cases of recurrent cryptogenic cirrhosis were seen. OLT for cryptogenic cirrhosis is associated with a poor outcome compared with other indications, hepatitis of uncertain origin occurred in 22% of cryptogenic recipients surviving longer than 6 months, and no evidence of recurrence of cryptogenic cirrhosis was seen thus far in follow-up.

Adolescent↗
PubMed1997

Skeletal muscle myosin heavy chain synthesis in type 1 diabetes.

Although insulin's anticatabolic effect on protein metabolism in type 1 diabetes has been clearly shown to be related to the inhibition of protein breakdown, insulin's effect on muscle protein synthesis remains controversial. Cross-limb studies and measurements of synthesis rates of mixed muscle protein have yielded conflicting results. These measurements represent the mean synthesis of several muscle proteins and may miss changes in the synthesis rates of individual muscle proteins. We measured the fractional synthesis rates of myosin heavy chain (MHC), the principal muscle contractile protein, and mixed muscle protein (MMP) in six type 1 diabetic patients during insulin deprivation and insulin treatment. Comparisons were made with six healthy control subjects. Muscle biopsies were taken at 2 h and 8 h during a primed continuous infusion of L-[1-13C]leucine. MHC was purified by a preparative continuous elution gel electrophoresis, and fractional synthesis rates were calculated. We found that in type 1 diabetic subjects, the fractional synthesis rates of MHC and MMP during insulin treatment are similar to those of control subjects. Acute insulin deprivation did not affect either the synthesis rate or the ratio of MHC to MMP in type 1 diabetic subjects. In the postabsorptive state, acute insulin deprivation has no effect on MHC or MMP synthesis in type 1 diabetic patients.

Adult↗
PubMed1996

Evidence for a catabolic role of glucagon during an amino acid load.

Despite the strong association between protein catabolic conditions and hyperglucagonemia, and enhanced glucagon secretion by amino acids (AA), glucagon's effects on protein metabolism remain less clear than on glucose metabolism. To clearly define glucagon's catabolic effect on protein metabolism during AA load, we studied the effects of glucagon on circulating AA and protein dynamics in six healthy subjects. Five protocols were performed in each subject using somatostatin to inhibit the secretion of insulin, glucagon, and growth hormone (GH) and selectively replacing these hormones in different protocols. Total AA concentration was the highest when glucagon, insulin, and GH were low. Selective increase of glucagon levels prevented this increment in AA. Addition of high levels of insulin and GH to high glucagon had no effect on total AA levels, although branched chain AA levels declined. Glucagon mostly decreased glucogenic AA and enhanced glucose production. Endogenous leucine flux, reflecting proteolysis, decreased while leucine oxidation increased in protocols where AA were infused and these changes were unaffected by the hormones. Nonoxidative leucine flux reflecting protein synthesis was stimulated by AA, but high glucagon attenuated this effect. Addition of GH and insulin partially reversed the inhibitory effect of glucagon on protein synthesis. We conclude that glucagon is the pivotal hormone in amino acid disposal during an AA load and, by reducing the availability of AA, glucagon inhibits protein synthesis stimulated by AA. These data provide further support for a catabolic role of glucagon at physiological concentrations.

3-Hydroxybutyric Acid↗
PubMed1996

Protein metabolism and liver disease.

In health, the liver orchestrates the metabolism of proteins and amino acids. When the liver is diseased, the regulation of protein metabolism is frequently disturbed. The manifestations of disturbed protein metabolism in liver disease are varied and change with disease aetiology and severity. The hallmarks of protein and amino acid metabolism in liver disease are lowered concentrations of circulating branched-chain and increased concentrations of circulating aromatic amino acids with concomitantly altered amino acid kinetics. The changes in amino acid kinetics in liver disease are characterized by increased endogenous leucine flux, an indicator of protein breakdown, and leucine oxidation in the post-absorptive state (when calculated using a reciprocal-pool model and normalized for body cell mass). In addition, the increase in whole-body protein synthesis in response to an amino acid infusion may be attenuated in patients with cirrhosis. These changes are often accompanied by clinically apparent muscle wasting, manifest as protein-calorie malnutrition, and associated low levels of hepatically synthesized plasma proteins. While the pathogenesis of these changes in protein and amino acid metabolism has not been elucidated, altered levels of circulating hormones, known to affect protein metabolism, are probably important. Lowered levels of micronutrients and trace metals and elevated levels of cytokines may also play a role.

Humans↗