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ABSTRACT: Hepatitis C virus (HCV) recurrence with accelerated fibrosis following orthotopic liver transplantation (OLT) is a universal phenomenon. To evaluate mechanisms contributing to HCV induced allograft fibrosis/cirrhosis, we investigated HCV-specific CD4+Th17 cells and their induction in OLT recipients with recurrence utilizing 51 HCV+ OLT recipients, 15 healthy controls and 9 HCV- OLT recipients. Frequency of HCV specific CD4+ Tcells secreting IFN-γ, IL-17 and IL-10 was analyzed by ELISpot. Serum cytokines and chemokines were analyzed by LUMINEX. Recipients with recurrent HCV induced allograft inflammation and fibrosis/cirrhosis demonstrated a significant increase in frequency of HCV specific CD4+Th17 cells. Increased pro-inflammatory mediators (IL-17, IL-1β, IL-6, IL-8 and MCP-1), decreased IFN-γ, and increased IL-4, IL-5 and IL-10 levels were identified. OLT recipients with allograft inflammation and fibrosis/cirrhosis demonstrated increased frequency of Foxp3+ regulatory T cells (Tregs) that inhibited HCV specific CD4+Th1 but not Th17 cells. This suggests that recurrent HCV infection in OLT recipients induces an inflammatory milieu characterized by increased IL-6, IL-1β and decreased IFN-γ which facilitates induction of HCV specific CD4+Th17 cells. These cells are resistant to suppression by Tregs and may mediate an inflammatory cascade leading to cirrhosis in OLT recipients following HCV recurrence.
American Journal of Transplantation 04/2011; 11(4):775-85. · 6.39 Impact Factor
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Anesthesiology 01/2002; 95(6):1523-4. · 5.36 Impact Factor
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J S Crippin
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ABSTRACT: 1. Bone disease is a common problem in patients with chronic liver disease and liver transplants. 2. The cause of bone disease in these patients is multifactorial. 3. Bone disease worsens initially after liver transplantation, with subsequent improvement over time. However, bone disease in liver transplant recipients is common with long-term follow-up. 4. Evaluation of these patients should include metabolic and hormonal evaluations in conjunction with dual energy x-ray absorptiometry or bone mineral density evaluation. 5. Treatment with calcium, vitamin D, and hormonal supplements should be considered when appropriate for patients awaiting and after liver transplantation. The use of bisphosphanates and calcitonin also should be considered, although published studies in these populations are few in number.
Liver Transplantation 12/2001; 7(11 Suppl 1):S27-35. · 3.39 Impact Factor
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Transplantation 05/1999; 67(9):S596. · 4.00 Impact Factor
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C R Gross,
M Malinchoc,
W R Kim,
R W Evans,
R H Wiesner,
J L Petz, J S Crippin,
G B Klintmalm,
M F Levy,
P Ricci,
T M Therneau,
E R Dickson
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ABSTRACT: Liver transplantation (LT) is an established therapy for patients with end-stage primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). In this report, we describe the health status and quality of life (QOL) in patients with these cholestatic liver diseases before and after LT. A QOL questionnaire was completed by 157 adult patients with PBC or PSC before and 1 year after liver transplantation at the Mayo Clinic or Baylor University Medical Center. This questionnaire measured four aspects of QOL, including symptoms; physical, social, and emotional functioning; health perceptions; and overall QOL. Changes in these QOL parameters before and after LT were described, and regression analysis was used to assess the relationships between clinical and QOL factors. There were no differences in QOL parameters between patients with PBC and PSC. QOL following transplantation was substantially better than before transplantation. This was observed in all four aspects of QOL. The degree of improvement as measured by effect size (difference in mean scores divided by the pretransplantation standard deviation) was 0.53 for symptoms (P <.01), 1.16 for function (P <.01), 2.37 for health satisfaction (P <.01), and 1.16 for overall QOL (P <.01). Patients' overall QOL before transplantation was significantly related to subjective and objective health status indicators and clinical factors such as ascites and renal dysfunction. QOL at 1-year follow-up, however, could not be adequately predicted by the pretransplantation subjective health status and clinical factors. Patients with end-stage cholestatic disease undergoing LT experience substantial improvement in all aspects of QOL addressed in this study. The patients' QOL 1 year after LT could not be predicted by pretransplantation variables used in this study.
Hepatology 03/1999; 29(2):356-64. · 11.66 Impact Factor
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F V Schiodt,
E Atillasoy,
A O Shakil,
E R Schiff,
C Caldwell,
K V Kowdley,
R Stribling, J S Crippin,
S Flamm,
K A Somberg,
H Rosen,
T M McCashland,
J E Hay,
W M Lee
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ABSTRACT: Little information is available on acute liver failure (ALF) in the United States. We gathered demographic data retrospectively for a 2-year period from July 1994 to June 1996 on all cases of ALF from 13 hospitals (12 liver transplant centers). Data on the patients included age, hepatic coma grade on admission, presumed cause, transplantation, and outcome. Among 295 patients, 74 (25%) survived spontaneously, 121 (41%) underwent transplantation, and 99 (34%) died without undergoing transplantation. Ninety-two of 121 patients (76%) survived 1 year after transplantation. Acetaminophen overdose was the most frequent cause (60 patients; 20%), followed by cryptogenic/non A non B non C (NANBNC; 15%), idiosyncratic drug reactions (12%), hepatitis B (10%), and hepatitis A (7%). Spontaneous survival rates were highest for patients with acetaminophen overdose (57%) and hepatitis A (40%) and lowest for those with Wilson's disease (no survivors of 18 patients). The transplantation rate was highest for Wilson's disease (17 of 18 patients; 94%) and lowest for autoimmune hepatitis (29%) and acetaminophen overdose (12%). Age did not differ between survivors and nonsurvivors, perhaps reflecting a selection bias for patients transferred to liver transplant centers. Coma grade on admission was not a significant determinant of outcome, but showed a trend toward affecting both survival and transplantation rate. These findings on retrospectively studied patients from the United States differ from those previously gathered in the United Kingdom and France, highlighting the need for further study of trends in each country.
Liver transplantation and surgery: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 02/1999; 5(1):29-34.
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D R Jeyarajah,
G J Netto,
S P Lee,
G Testa,
O Abbasoglu,
B S Husberg,
M F Levy,
R M Goldstein,
T A Gonwa,
G W Tillery, J S Crippin,
G B Klintmalm
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ABSTRACT: The possibility of primary sclerosing cholangitis (PSC) recurrence after liver transplantation has been debated. The aim of this study is to examine whether recurrent PSC and chronic rejection (CR) are different expressions of the same disease process.
One hundred consecutive patients receiving 118 grafts for the diagnosis of PSC were reviewed and placed into three groups: group A, recurrent disease, as evidenced by cholangiographic and pathologic findings with radiographic arterial flow to the liver (n=18; 15.7%); group B, those who developed CR (n=15; 13.0%); and group C, all others (n=82; 71.3%). Cholangiograms and histopathologic specimens were examined in a blinded fashion.
Demographic factors were similar, except for age, with a significantly younger age and more episodes of rejection in groups A and B (P<0.03). Group A had a higher incidence of cytomegalovirus hepatitis (P=0.008). Five-year graft survivals for A, B, and C were 64.6%, 33.3%, and 76.1%, respectively (P=0.0001), 5-year patient survivals were 76.2%, 66.7%, and 89.1%, respectively (P=0.0001), and repeat transplantation rates were 27.8%, 46.7%, and 8.5%, respectively (P=0.005). Radiographically, 90% of cholangiograms in patients with recurrent disease showed at least multiple intrahepatic strictures. Histopathologically, patients with recurrent disease and CR shared many features.
We have described a high incidence of recurrent PSC and CR in patients who received transplants for PSC. Histopathologic analysis suggests that CR and recurrent PSC could represent a spectrum of indistinguishable disease. However, the distinct difference in clinical outcome, as evidenced by an increased repeat transplantation rate and lower graft and patient survival in the CR group, clearly suggests that they are two distinct entities that require very different treatment strategies.
Transplantation 12/1998; 66(10):1300-6. · 4.00 Impact Factor
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J S Crippin
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ABSTRACT: Orthotopic liver transplantation for primary biliary cirrhosis and primary sclerosing cholangitis is a well-accepted therapy for complications of end-stage liver disease and is associated with an excellent outcome in the majority of cases. However, transplant centers are striving to improve on these outcomes by studying ways to optimize the timing of transplantation. Several natural history and prognostic models for both primary biliary cirrhosis and primary sclerosing cholangitis have been derived from the study of large populations of patients in an attempt to predict long-term rates of survival. In addition, models exist to predict resource utilization after liver transplantation. Other factors besides complications of end-stage liver disease may also be indications for transplantation, including refractory pruritus, recurrent bacterial cholangitis in patients with primary sclerosing cholangitis, hepatic osteodystrophy, and a poor quality of life.
Liver transplantation and surgery: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 10/1998; 4(5 Suppl 1):S2-8.
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ABSTRACT: Hepatitis C chronically infects approximately 1.5% of Americans and is the most common clinical problem facing hepatologists. Since the virus was initially described in 1989, development of an effective therapy has been challenging. Although several different therapeutic agents have been used, no therapy has been shown to reliably eradicate the virus. Interferon-alpha, a cytokine with immunostimulatory and anti-viral properties, has become the therapy of choice for patients with chronic hepatitis C infection. Trials assessing the efficacy of interferon-alpha have characterized host and viral factors predictive of responses to treatment. A thorough understanding of these predictive factors is requisite to providing cost-effective therapeutic decisions for the patient with chronic hepatitis C infection.
Alimentary Pharmacology & Therapeutics 07/1998; 12(6):509-18. · 3.77 Impact Factor
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ABSTRACT: In 1989, we reported on the efficacy of liver transplantation in primary biliary cirrhosis (PBC) by demonstrating that the actual patient survival following transplantation was significantly better than without transplantation as predicted by a mathematical survival model ("Mayo natural history model"). Our aim in this investigation was to determine an optimal time to perform liver transplantation in PBC. One hundred forty-three patients with PBC undergoing liver transplantation were followed prospectively. Disease severity was measured immediately before transplantation by a summary score ("risk score") used in the Mayo natural history model, namely age, bilirubin, albumin, prothrombin time, and the presence or absence of edema. Proportional hazards analyses were performed assessing patient survival following transplantation. The influence of disease severity immediately pretransplantation on resource utilization for liver transplantation was assessed. Compared with our report in 1989, liver transplantation was performed at an earlier stage of disease (e.g., median risk score: 7.5 vs. 8.3; P < .01). Following transplantation, patient survival probabilities at 1, 2, and 5 years were 93%, 90%, and 88%, respectively. In the proportional hazards analysis, the risk of death following transplantation remained low until reaching a risk score of 7.8. In contrast, risk scores greater than 7.8 were associated with a progressively increased mortality. Resource utilization measured by the days in the intensive care unit (ICU) and hospital and the requirement for intraoperative blood transfusions was significantly greater in recipients who had higher risk scores before transplantation. Our data suggest that an optimal timing for liver transplantation, as determined by patient survival and resource utilization, appears to be at a risk score around 7.8 in patients with PBC.
Hepatology 07/1998; 28(1):33-8. · 11.66 Impact Factor
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ABSTRACT: Gastric infection with herpes simplex virus is rare, with only two cases previously reported. At the time of the previous reports, the virus could not be cultured, and the diagnosis was based on histological findings. Two cases of culture positive herpes simplex virus gastritis are presented, emphasizing the importance of routine gastric biopsies and viral cultures in immunodeficient patients with dyspeptic symptoms.
The American Journal of Gastroenterology 12/1997; 92(11):2116-7. · 7.28 Impact Factor
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P Ricci,
T M Therneau,
M Malinchoc,
J T Benson,
J L Petz,
G B Klintmalm, J S Crippin,
R H Wiesner,
J L Steers,
J Rakela,
T E Starzl,
E R Dickson
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ABSTRACT: We studied the outcome of 436 patients with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) who underwent orthotopic liver transplant (OLT) at three major liver transplant centers. Univariate predictors of outcome included age, Karnofsky score, Child's class, Mayo risk score, United Network for Organ Sharing (UNOS) status, nutritional status, serum albumin, serum bilirubin, international normalized ratio, and the presence of ascites, encephalopathy, renal failure (serum creatinine > 2 mg/dL), and edema refractory to diuretics. Using these predictors, we developed a four variable mathematical prognostic model to help the liver transplant physician predict the following: 1) the amount of intraoperative blood loss; 2) the number of days in the intensive care unit (ICU); and 3) severe complications after surgery. The model uses age, renal failure, Child's class, and United Network for Organ Sharing status. This study is the first to model the outcome of liver transplant in patients with a specific etiology of chronic liver disease (PBC or PSC). The model may be used to help select patients for OLT and to plan the timing of their transplantation.
Hepatology 03/1997; 25(3):672-7. · 11.66 Impact Factor
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Transplantation Proceedings 11/1996; 28(5):2786-7. · 1.00 Impact Factor
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J S Crippin
Liver transplantation and surgery: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 10/1996; 2(5 Suppl 1):64-72.
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ABSTRACT: Hepatic parenchymal iron deposition is a well-known complication of chronic hepatic inflammatory states. This can make the differential between chronic hepatitis and hereditary hemochromatosis difficult, however. The case of a 13-yr-old male with chronic hepatitis C and hereditary hemochromatosis resulting in end stage liver disease and the need for orthotopic liver transplantation is described. There has been no previously described case of the coexistence of these two diseases in a pediatric patient, resulting in end stage liver disease. The progression to cirrhosis in a patient of this age suggests a more rapid progression of the combined diseases than with either disease alone.
The American Journal of Gastroenterology 08/1996; 91(7):1427-9. · 7.28 Impact Factor
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ABSTRACT: Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase activities with hepatic steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Our aim was to conduct a pilot study to evaluate the safety and estimate the efficacy of ursodeoxycholic acid (UDCA) and clofibrate in the treatment of NASH. Forty patients were diagnosed with NASH based on a compatible liver biopsy with other causes of liver disease, including alcohol abuse, excluded by history, serum tests, and use of ultrasound. Twenty-four patients received 13 to 15 mg/kg/d of UDCA for 12 months. Sixteen patients with hypertriglyceridemia were placed on clofibrate, 2 g/day for 12 months. Twenty-five women and 15 men entered the study. Six of 40 patients (15%) withdrew because of side effects. Four additional patients were withdrawn because of noncompliance; one of them later required liver transplantation. In the UDCA group, the decreases in mean serum levels of alkaline phosphatase, alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) as well as histological grade of steatosis were significant. Among the patients treated with clofibrate, no change from baseline was found in mean ALT, aspartate transaminase (AST), GGT, bilirubin, triglycerides, and cholesterol, or in histological grade of steatosis, inflammation, or fibrosis after 12 months of treatment as compared with entry. Alkaline phosphatase activities decreased significantly from baseline. Despite the known lipid-lowering effects of clofibrate, it did not appear to be of clinical benefit in the treatment of NASH in this 1-year pilot study. However, treatment of NASH with UDCA for 12 months resulted in significant improvement in alkaline phosphatase, ALT, GGT, and hepatic steatosis. The possible benefit of UDCA therapy should be further investigated in the context of a randomized, controlled trial.
Hepatology 07/1996; 23(6):1464-7. · 11.66 Impact Factor
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Transplantation Proceedings 03/1995; 27(1):1204-5. · 1.00 Impact Factor
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ABSTRACT: Ursodeoxycholic acid (UDCA) has been proposed as beneficial therapy for patients with primary biliary cirrhosis (PBC). The effects of UDCA on metabolic bone disease, a major source of morbidity in patients with PBC, are essentially unknown. Preliminary information suggests that UDCA may improve biochemical indices of bone disease, although information about the effects of UDCA on bone density is lacking. In this study, we describe the effects of UDCA on lumbar spine bone mineral densities over a 3-year period during which patients were enrolled in a randomized, double-blind, therapeutic trial of UDCA for the treatment of PBC. Lumbar spine dual-photon densitometry was measured at entry and annually. Eighty-eight patients, 50 in the UDCA group and 38 in the placebo group, had serial measurements available for up to 3 years. There was no statistical difference between the two treatment groups at entry with respect to histological stage, total bilirubin, age, use of calcium supplement, vitamin D levels, or estrogen. After 3 years of treatment, there was no significant difference in the lumbar spine bone densitometry measurements between the UDCA-treated and placebo groups. We conclude that, after 3 years of treatment, UDCA is not associated with statistically significant differences in the rate of bone loss from the lumbar spine in patients when compared with placebo despite beneficial effects of treatment on the underlying liver disease. Further efforts to define effective treatments for the bone disease need to be pursued.
Hepatology 03/1995; 21(2):389-92. · 11.66 Impact Factor
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ABSTRACT: Osteoporosis is a frequent extrahepatic complication of primary biliary cirrhosis. Although histologically similar to the osteoporosis commonly seen in postmenopausal females, the pathogenesis and management of bone disease in patients with primary biliary cirrhosis is poorly understood. The experience with a subgroup of patients with primary biliary cirrhosis treated with vitamin D, calcium, and estrogen supplementation was reviewed to determine the effects of medical treatment on hepatic osteodystrophy.
The records of 203 women with the diagnosis of primary biliary cirrhosis were reviewed retrospectively for lumbar spine bone mineral density, menopausal status, and supplementation with vitamin D, calcium, and estrogen.
The 16 postmenopausal patients treated with estrogen replacement had a statistically significant increase in the lumbar spine bone mineral density at 1 yr (+0.014 +/- 0.049 vs. -0.03 +/- 0.046 g/cm2, p < 0.038), without a significant change in the serum bilirubin or alkaline phosphatase. In treated patients, vitamin D and calcium supplementation did not lead to significant improvement in lumbar spine bone mineral density.
Calcium and vitamin D supplementation, even in the presence of vitamin D deficiency, do not improve lumbar spine bone mineral density in patients with primary biliary cirrhosis. Estrogen replacement in postmenopausal patients, however, does appear to improve lumbar spine bone mineral density without increasing clinical or biochemical cholestasis, a potential complication reported in animal studies. This study should serve as an impetus for a controlled trial of estrogen replacement in postmenopausal patients with primary biliary cirrhosis.
The American Journal of Gastroenterology 01/1994; 89(1):47-50. · 7.28 Impact Factor
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J S Crippin
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ABSTRACT: Potentiation of acetaminophen hepatotoxicity has previously been associated with a history of alcohol abuse. Presented here is the case of a 21-yr-old Philippino female with rapidly deteriorating hepatic functions. She had been on isoniazid, 300 mg daily, as prophylaxis against tuberculosis due to a positive tuberculin skin test. She took 3.25 g of acetaminophen for abdominal cramping and subsequently had rapid deterioration of liver function manifested by prolongation of the prothrombin time, elevated ammonia, marked elevation of transaminases, and hyperbilirubinemia. Over the course of 1 wk, these values essentially normalized and she was discharged. Isoniazid induces the cytochrome P-450 system, resulting in increased metabolism of acetaminophen, formation of toxic metabolites, depletion of glutathione stores, and subsequent hepatocellular injury. Patients on isoniazid should use caution when taking acetaminophen since the potentially hepatotoxic effects may be amplified due to induction of the cytochrome P-450 system.
The American Journal of Gastroenterology 05/1993; 88(4):590-2. · 7.28 Impact Factor
