Adverse events with telaprevir in half of California HIV/HCV group

Provided by IAS

Author: Mark Mascolini

08 January 2014

Half of 24 patients coinfected with HIV and hepatitis C virus had serious adverse events when taking the HCV protease inhibitor telaprevir with pegylated interferon and ribavirin.

Telaprevir was one of the first HCV protease inhibitors licensed for use against infection with genotype 1 HCV, but its impact in people with HIV is still being assessed. Prescribing information warns about serious skin reactions, anemia, fatigue, vomiting, and other possible complications with telaprevir. Its use is contraindicated with strong CYP3A inhibitors and inducers, which include many antiretrovirals.

This retrospective cohort study involved HIV/HCV-coinfected people treated with telaprevir plus pegylated interferon and ribavirin at the University of California, San Diego HIV clinic.

Among 24 consecutive patients, serious adverse events developed in 12 (50%). Seven patients (29%) had to stop HCV therapy because of adverse events, “despite an intensive multidisciplinary monitoring approach.”

The authors suggest that “careful consideration of the risks and benefits of telaprevir-based therapy should be undertaken, given prospects for interferon-sparing therapy in the near future.”

The United States Food and Drug Administration has licensed three other direct-acting HCV antivirals: boceprevir, sofosbuvir, and simeprevir

Source: Edward R. Cachay, David L. Wyles, Francesca J. Torriani, Craig Ballard, Bradford Colwell, Jennifer C. Lin, Lucas Hill, William C. Mathews. High incidence of serious adverse events in HIV-infected patients treated with a telaprevir-based hepatitis C virus treatment regimen. AIDS. 2013; 27: 2893-2897.

For the study abstract
(Downloading the complete article requires a subscription to AIDS or an online payment; the abstract is free.)

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Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment

Antimicrob Agents Chemother. 2013 Dec;57(12):6097-105. doi: 10.1128/AAC.00608-13. Epub 2013 Sep 30.

Brennan BJ, Wang K, Blotner S, Magnusson MO, Wilkins JJ, Martin P, Solsky J, Nieforth K, Wat C, Grippo JF.

Abstract

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0-12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0-12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.

PMID: 24080649 [PubMed - in process] PMCID: PMC3837852  [Available on 2014/6/1]

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My HCV Story by Debbie Cole

January 08, 2014

When I was pregnant for my son in 1992, I found out that my blood is O-. I had always thought it is O+. I decided that after my pregnancy I would be an active blood donor. I lived up to that promise until 2002. I gave my last blood donation to the Red Cross in February 2002. I was even a member of the O- Club the Red Cross has.

In May 2002 I went in the hospital for “simple” hernia surgery. I ended up having two pulmonary emboli, three major surgeries, prolonged hospital stays, days and weeks in the ICU, and numerous blood transfusions. I was closely monitored by my doctors and specialists months after my last hospital stay. I was on blood thinners for months, and so I would have to have my blood tested every couple weeks.

After about a year, my internist said that he was going to do a hepatitis test. He indicated that my liver enzyme levels had been steadily rising. I checked back with him a few weeks later, and he told me that I had Hepatitis C (HCV). I wasn’t too worried, and I said to him that all I had to do was to take some drugs and I would be okay. A friend of mine in the medical profession had hepatitis (later learned it was Hepatitis A), took medication, and was fine. My doctor said that I was

mistaken. HCV could be fatal, if left untreated. He referred me to a gastroenterologist. I read all I could about HCV, and I read about Naomi Judd, as she was someone I had heard about having HCV.

I went to my mother’s gastroenterologist…bad choice. He asked about my marital status (married, at the time) and risk factors. I told him that I had a rocky marriage and only risk factors were my blood transfusions. He told me that I didn’t get HCV from blood transfusions – he said blood supply is fine now. He said I must have gotten it from sleeping around (I have had only 1 sex partner in my life, and that was my husband). I was horrified and shocked. I was too shocked to say anything. He told me I was too fat to have a liver biopsy, as I would bleed. Need-less-to-say, I didn’t go back to him.

I found another gastroenterologist, and he believed that I probably received the virus through the blood transfusions. He set up the liver biopsy, and it was found that I had genotype 1. I ended up doing the combination therapy for a year. I responded immediately to treatment. I had days that were really rough, and the headaches were awful. My gastro had given me a prescription for an antidepressant early in the treatment, and I think that helped. I have been in remission since 2005!

I would like to help raise awareness for this disease, as I have learned that so many people are so ignorant about this disease.

Ocera Therapeutics Announces Enrollment of the First Patient in a Phase IIb Study for Treatment of Acute Hepatic Encephalopathy

Ammonia Scavenger Ornithine Phenylacetate (OCR-002) Granted Orphan Disease and Fast Track Status

PALO ALTO, Calif., Jan. 8, 2014 (GLOBE NEWSWIRE) -- Ocera Therapeutics (Nasdaq:OCRX) today announced enrollment of the first patient in its multi-center Phase 2b study, the "STOP-HE" or OCR002-HE209 trial. This study is evaluating the efficacy, safety and pharmacokinetics of OCR-002, or ornithine phenylacetate, in hospitalized patients with liver cirrhosis and an acute episode of hepatic encephalopathy (HE). HE is a serious complication of liver failure and decompensated cirrhosis in the setting of chronic liver disease, where elevation of ammonia concentration in the blood and brain can lead to deterioration of neurocognitive function, ranging from subtle abnormalities to frank (overt) disorientation, stupor, coma and death. OCR-002 is a novel molecule, an ammonia scavenger which is intended to rapidly reduce the concentration of ammonia in the blood when administered as a continuous intravenous infusion. OCR-002 has been granted orphan drug designation by the US Food and Drug Administration (FDA) for the treatment of hyperammonemia and resultant HE in patients with acute liver failure or acute on chronic liver disease.

"HE is a serious disorder that leads to approximately 150,000 hospitalizations per year in the United States and for which the best available treatments are still suboptimal. We need better and more effective treatments," said Robert Brown M.D., Frank Cardile professor of medicine and pediatrics and director, Center for Liver Disease and Transplantation, Columbia University and a principal investigator in the Ocera Phase 2b study.

The study is a randomized double-blind, controlled study of OCR-002 plus current standard of care versus standard of care alone. The study will enroll 200 patients at approximately 40 centers in the United States and Canada. The trial will assess time to achievement of meaningful improvement in HE symptoms. Ocera anticipates completing the study in early 2015.

"We are excited to begin enrolling patients in the Phase 2b study," said Linda Grais, M.D., J.D., CEO of Ocera. "The number of hospitalizations for HE has been increasing steadily over the past decade and we are eager to help these seriously ill patients."

About Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a complication of patients with liver cirrhosis, acute liver failure and acute liver injury. When the liver is no longer able to function normally, there is an accumulation of ammonia in the blood because usual metabolic pathways are impaired. Ammonia elevation impairs brain cell function, and can lead to overt neurocognitive impairment that frequently occurs as acute episodes in the setting of cirrhosis following the occurrence of an inciting factor, such as gastrointestinal bleeding or infection. An acute overt episode of HE is marked by impaired cognition, lethargy, disorientation and a decreased level of consciousness. HE can lead to coma and death due to brain swelling. There are no current drug treatments on the market in the United States for HE that can be given intravenously to hospitalized patients with an acute HE episode.

About Ocera

Ocera Therapeutics, Inc. is a clinical stage biopharmaceutical company focused on the development and commercialization of OCR-002 (ornithine phenylacetate). OCR-002 is an ammonia scavenger which has been granted Orphan Disease and Fast Track status from the FDA to treat hyperammonemia and associated hepatic encephalopathy in patients with liver cirrhosis, acute liver failure and acute liver injury. For additional information, please see www.ocerainc.com.

Forward Looking Statements

This press release contains "forward-looking" statements, including, without limitation, all statements related to the OCR-002 clinical development program, including patient enrollment estimates, expected timing for the receipt of clinical data, and the potential success of OCR-002 in clinical trials. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "believe," "expected," "hope," "plan," "potential," "will" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Ocera's current expectations. Forward-looking statements involve risks and uncertainties and Ocera's actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, including those risks and uncertainties discussed under the heading "Risk Factors" in Ocera's Quarterly Report on Form 10-Q for the quarter ended September 30, 2013 filed on November 14, 2013, as well as other risks detailed in Ocera's subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Ocera undertakes no duty to update this information unless required by law.

CONTACT:
Inquiries:
Jeri Hilleman  
Ocera Therapeutics, Inc.
communications@ocerainc.com  
650-475-0158

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Changing Pattern of Donor Selection Criteria in Deceased Donor Liver Transplant: A Review of Literature

Journal of Clinical & Experimental Hepatology
Volume 3, Issue 4 , Pages 337-346, December 2013

Dronacharya Routh, Sudeep Naidu, Sanjay Sharma, Priya Ranjan, Rajesh Godara

Received 18 November 2013; accepted 18 November 2013. published online 25 November 2013.

During the last couple of decades, with standardization and progress in surgical techniques, immunosuppression and post liver transplantation patient care, the outcome of liver transplantation has been optimized. However, the principal limitation of transplantation remains access to an allograft. The number of patients who could derive benefit from liver transplantation markedly exceeds the number of available deceased donors. The large gap between the growing list of patients waiting for liver transplantation and the scarcity of donor organs has fueled efforts to maximize existing donor pool and identify new avenues. This article reviews the changing pattern of donor for liver transplantation using grafts from extended criteria donors (elderly donors, steatotic donors, donors with malignancies, donors with viral hepatitis), donation after cardiac death, use of partial grafts (split liver grafts) and other suboptimal donors (hypernatremia, infections, hypotension and inotropic support).

Keywords: extended criteria donor, liver transplantation, donor pool

Abbreviations: LT, liver transplantation, ECD, extended criteria donor, DCD, donation after cardiac death, PNF, primary nonfunction, DGF,delayed graft function, LDLT, living donor liver transplantation, SLT, split liver transplantation, CIT, cold ischemia time, MELD, Model for End-Stage Liver Disease, SRTR, Scientific Registry of Transplant Recipients, SOFT, survival outcomes following liver transplantation, mTOR,mammalian target of rapamycin inhibitors, HIV, human immunodeficiency virus, HBV, hepatitis B virus, HCV, hepatitis C virus, HBIg, hepatitis B immune globulin, HTLV, human T-lymphotropic virus, NRP, normothermic regional perfusion, ECMO, extra corporeal membrane oxygenation

Liver transplantation (LT) has been the only proven treatment for patients with end-stage liver disease or hepatocellular carcinoma in cirrhotic patients. However, with increasing success in the outcome of LT there has been further expansion of indications. Thus with the widening of indications the demand for organs has been increasing steadily and exceeds the number of available deceased donors. Gradually, live donation and technically modified grafts were introduced and accepted as a means of enhancing the donor organ pool. Unlike India and Asian countries most transplant centres in the world still depend on the deceased donor pool as opposed to live donation.

A major challenge for the transplant community is to develop strategies to close the gap between the number of patients in need of a transplant and the number of available organs. One of the main strategies to address this discrepancy is expansion of the Deceased Donor pool utilizing extended criteria donor (ECD) and donation after cardiac death (DCD) donors.¹, ², ³ This can be done by using organs that were previously thought to be associated with a high risk of primary nonfunction (PNF) or delayed graft function (DGF), the so-called ECD or marginal livers³, ⁴ (i.e., donors with steatosis, with malignancies, with viral infections, older or elderly donors, DCD, etc). These livers considered unacceptable for transplantation in the past, are now being considered for transplantation. Another way to expand the donor pool is through advances in medical practice, particularly surgical techniques including living donor liver transplantation (LDLT) and split liver transplantation (SLT). Although the ECD organs may not be optimal, the high death rate on the waiting lists has forced transplant surgeons to make a stark choice between dying without a liver and proceeding with a liver that was perhaps not ideal.¹, ², ³, ⁴ It is also known that the marginal grafts exhibit poor tolerance to ischemia/reperfusion (I/R) injury, which is an important cause of liver damage occurring during surgical procedures including hepatic resections and LT.¹, ³

Change in donor characteristics: natural history 

There has been a paradigm shift in the organ donation trends over the last couple of decades. During the era of expansion of automobile industry with minimal road safety measures, the majority of deceased donors consisted young victims of road traffic accidents. These donors were less likely to have steatosis and in the absence of significant comorbidity, their liver function was more likely to be good at the time of donation. However, with improved road safety measures there has been a decrease in the number and severity of traffic accidents and fewer trauma patients as potential donors. The current socioeconomic trend has shown that donors are more likely to be obese than before and with increase in the average life expectancy of people more potential donors are likely to be in advancing age group and may have active or previous history of treated malignancy.⁵ So if we go by the original yardstick of an “ideal” donor, then these factors will probably make a donor “extended criteria donor or marginal donor”.⁶, ⁷

Ideal donor: definition

An ideal or reference donor was defined according to the following criteria: age below 40 years, trauma as the cause of death, donation after brain death, hemodynamic stability at the time of procurement, no steatosis or any other underlying chronic liver lesion, and no transmissible disease.⁸, ⁹ A reference donor implies a very low risk of initial poor function or early allograft failure leading to death or requiring re-transplantation. An ideal allograft is different from an ideal donor. The ideal allograft category may be influenced by variables that are introduced following procurement, such as the prolonged ischemia time (CIT), or technical variants, such as those occurring with allograft reduction (e.g., split liver allograft). These variables should not be included in the definition of ECD because the aim is to assess risk at procurement.

Extended criteria donor: definition 

An extended criteria donor implies higher risk in comparison with a reference donor. The risk may manifest as increased incidence of poor allograft function, allograft failure, or transmission of a donor-derived disease. Adhering to strict donor selection criteria is safe but unlikely to help reduce transplant wait list mortality. Exploring the possibility of using grafts from extended criteria donors is advantageous in many ways. Provided the decision-making is performed with a “utilitarian” approach, sicker patients are likely to face less competition on the wait list whenever a “conventional” or good quality graft becomes available. In turn, this may help reduce the transplant wait list mortality benefiting the largest number of recipients.¹⁰

Donor characteristics in liver transplant: how important is it? 

With increasing gap between donor organ availability and patients in need of transplantation, the use of marginal high risk or ECD organs has increased.¹¹ Though priority in liver allocation is based on the Model for End-Stage Liver Disease (MELD) score, donor-recipient matching occurs at the time of organ procurement and transplantation, and substantial selection is involved in accepting an organ.¹² The identification of donor-related factors that portend poor posttransplant outcomes and analysis that can guide the use of organs according to donor characteristics have become increasingly important,¹³especially because donor characteristics and medical management vary by region and organ procurement organization and may affect posttransplant outcomes.⁸The most important donor factor is age, which has repeatedly been shown to be a significant predictor of allograft failure and posttransplant death.⁸, ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷ This is especially true for patients undergoing transplantation for HCV; outcomes are significantly worse for patients with HCV who receive livers from older donors. Less is understood about the effects of older donor allografts, especially with respect to long-term outcomes, in non-HCV recipients. The type of donor is also important; the use of DCD livers is associated with an increased risk of posttransplant allograft failure.¹⁸, ¹⁹ The MELD score is an excellent predictor of wait list mortality but a suboptimal predictor of posttransplant allograft and patient survival because of donor, recipient, and transplant characteristics and unpredictable posttransplant events (e.g., patient compliance, allograft primary nonfunction, and hepatic artery thrombosis). Objective parameters that quantify the risk associated with donor organs are actively being sought. Several mathematical models have been proposed to identify predictors of allograft and patient survival after liver transplantation.

Feng, et al,⁸ analyzed 20,000 transplants from the Scientific Registry of Transplant Recipients (SRTR) database and developed a DRI, which is calculated from seven donor and two transplant variables that were found to be independently associated with an increased risk of graft failure. These included donor >40 years, donor height, donation after cardiac death, split/partial grafts, cerebrovascular accident or other cause of death (except trauma, stroke, or anoxia), cold ischemia time, and organ sharing outside the local donor service area. Although a conclusive statement on the impact of graft steatosis could not be made due to incomplete data in the registry, the analysis of Feng, et al,⁸ highlights the relevant donor risk factors and supports a clear correlation between organ quality and post-transplantation outcome.

Similarly, Rana et al²⁰ identified 13 recipient factors, 4 donor factors, and 2 operative factors (warm and cold ischemia times) as significant predictors of recipient mortality 3 months after transplantation, using MELD era data and including retransplants. Using 18 risk factors, (excluding the warm ischemia time), the survival outcomes following liver transplantation (SOFT) score successfully predicted 3-month recipient survival. The SOFT score included the MELD score at the time of transplantation (categorized as >30 or <30). In their analysis of predicting 3-month mortality after liver transplantation, the concordance statistic was 0.63 for the MELD score and 0.70 for the SOFT score. In comparison, the MELD score c statistic was greater than 0.85 for predicting wait list mortality.²¹ Donor race was not a significant predictor in this study. Concerns similar to those outlined previously and complex statistical modeling limit its widespread application. Furthermore, longer time periods are needed to judge successful transplants; 3-month mortality estimates may be highly influenced by perioperative factors, which may be indirectly related to transplant center characteristics.

Donor physiology and brain death prior to procurement 

Brain death is associated with a number of circulatory, metabolic, and hormonal changes eventually leading to somatic death and circulatory changes are the leading cause of organ dysfunction.²², ²³ There are no guidelines on the care of donors with respect to optimizing liver allograft function prior to procurement. Donor homeostasis has been defined by a mean arterial pressure between 65 and 100 mm Hg, urine output between 1 and 1.5 mL/kg/h, hemoglobin between 7 and 9 g/dL, normal arterial blood lactate, partial pressure of arterial oxygen over 80 mm Hg, temperature between 35.5 °C and 38 °C, and serum sodium below 150 mmol/L.²⁴ Accumulated data, both in animal models and in humans, have demonstrated dysfunction of the hypothalamic-pituitary-adrenal axis during brain death that leads to a decrease in circulating thyroid hormone and corticosteroids.²⁵ However, no clear evidence exists indicating that exogenous hormone therapy (thyroid hormones and/or corticosteroids) improves transplant outcomes.²⁶, ²⁷ Additional areas of future research include the potential usefulness of nutritional support, glycine, and N-acetyl cysteine.²⁸, ²⁹, ³⁰

Factors affecting the outcome of use of extended criteria donor 

Cold Ischemia Time 

Prolonged CIT is an independent risk factor for the development of delayed graft function and primary nonfunction.³¹Recipient survival was shown to be adversely affected by CIT over 12 h in a European survey and over 10 h in a US survey.³²,³³ The European Liver Transplant Registry survey showed that 5-year recipient survival was 57% with CIT over 15 h versus 64% with CIT between 12 and 15 h and 67% with CIT below 12 h.³⁴ Liver grafts from elderly donors and/or donors with steatosis are even more affected by prolonged CIT and preservation injury. In this group, optimal liver function can be best achieved when CITs are kept less than 8 h.³⁵ These results emphasize the need to shorten CIT as much as possible in the case of extended criteria donors.

Preservative Solutions 

The development of the University of Wisconsin (UW) preservation solution has dramatically improved the quality of preserved allografts.³⁶, ³⁷, ³⁸, ³⁹ They have been designed to reduce cellular injury during cold ischemia and minimize reperfusion injury. UW has been used throughout the world for more than 20 years but is now challenged by 3 other solutions—Celsior, histidine tryptophan ketoglutarate, and IGL-1—which are less expensive and potentially superior for organ preservation.⁴⁰, ⁴¹, ⁴² No difference in short-term or long-term outcomes has been observed for each of these 3 solutions in comparison with UW.⁴⁰, ⁴¹, ⁴², ⁴³ However, the study populations in the trials that have been reported so far are relatively small and nonselect groups of donors. The lower viscosity of histidine tryptophan ketoglutarate and Celsior may prove to be of benefit in select cases such as older donors and non-heart-beating donors in whom the microcirculation may be compromised.⁴⁴ IGL-1 is a low-viscosity solution that may be superior to UW for the preservation of steatotic grafts.⁴²Although UW still remains the leading preservation solution for livers, “a la carte” use of preservation solutions in specific situations is an attractive option until further studies clarify the benefits of each preservation solution. However, no evidence for the superiority of this approach has been proven. This will be an important field of research with possible implications for procurement-specific practices.

Donors with liver dysfunction 

Abnormal liver biochemistry per se do not preclude acceptance of these organs for transplantation.⁴⁵ Donor liver dysfunction should be evaluated in the context of the donor's general health at the time of organ offering, along with the preceding medical history. Very high levels of transaminases probably indicate a recent ischemic insult; commonly due to hypoperfusion or hypoxia that is seen in patients with cardiorespiratory arrest. The time elapsed between the primary ischemic insult and donor organ offering is of great importance: provided circulation and oxygenation are restored by means of adequate resuscitation, the liver has a greater potential for recovery and liver dysfunction is likely to improve with time. Therefore high transaminase levels in the donor should not be a reason to refuse such liver grafts. More importantly, the absence of metabolic disease or younger age may be considered in favor of using such grafts. The synthetic capacity of the liver is a useful way of analyzing estimated graft function post LT, and prothrombin time/international normalized ratio and bilirubin should be considered surrogate markers along with high transaminases. Metabolic acidosis in the presence of abnormal liver biochemistry is generally an unfavorable combination and liver grafts from such donors are more likely to result in inferior outcomes. Steatosis or fatty liver is also widely prevalent. Hepatic steatosis is frequent in deceased organ retrievals and live donors, and reported in 9%–26% of donors.⁴⁶, ⁴⁷, ⁴⁸ Given the steady increase in the mean age of diseased donors and the overall increase in the prevalence of obesity, it is expected a further increase in the prevalence of steatosis in both deceased donors and living donors.⁴⁹ The literature suggests poor outcomes following LT using grafts with moderate or severe steatosis.⁵⁰ Liver dysfunction resulting from any of the immediate pre-donation events mentioned above, on the background of a steatotic liver has a synergistic effect. With the added graft damage from ischemia reperfusion injury such grafts are more likely to fail. Careful evaluation of liver function is therefore important, and in the absence of a severe pre-morbid history even grafts with some degree of liver dysfunction can be used with caution.⁵¹ There are no definite guidelines on the upper limit of acceptable abnormal biochemistry. A downward trend in liver enzymes is very important in making such a decision therefore repeated blood tests at least 12 h apart from each other will be an advantage. It is likely that with advanced liver graft preservation techniques currently introduced into transplant practice even grafts with severe dysfunction prior to donation may be resuscitated.

Elderly donors 

Studies have proved that organs from younger and “healthy” donors have better outcomes. Donor age is traditionally considered a key parameter predicting graft function. With improved health care the average life expectancy in society is increasing, hence the average donor age is significantly higher than in the past. Donor age per se should not be used as a surrogate for organ quality, at least in liver transplantation. Elderly donors alone should not be considered a contraindication and donor age should be evaluated against the general health of the donor prior to organ donation. Absence of metabolic disease, especially diabetes or hyperlipidemic status is probable indicators that the donor lived a healthy life prior to the clinical event culminating in organ donation. Recent literature also supports the use of liver grafts from upper extremes of age.⁵² With careful evaluation of the donor history it should be possible to “accept” the best quality donors from this donor population of advancing age.⁵³, ⁵⁴

Donors with malignancy 

The incidence of cancer in donors is approximately 3%, and the risk of transmitting malignancy by transplantation of an organ is roughly 0.01%.⁵⁵, ⁵⁶, ⁵⁷ It can be reasonably assumed that the risk of malignancy increases with donor age, and this means that transplanting organs from elderly donors may increase the risk of transmitting defined and undefined malignancies. Independent of the organ transplanted the most frequently transmitted malignancies originate from central nervous system tumors, melanoma, renal cell carcinoma, and lung carcinoma. The risk of transmission is increased in the case of a metastatic malignancy in donors. In addition, tumor grade is an important risk factor, poor differentiation being associated with a higher risk of transmission.⁵⁷ Donors with documented history of malignancy are not necessarily discarded. Donors with low-grade malignancies treated years ago (other than melanoma, hematological malignancies) or donors with low-grade central nervous system tumors and an especially low risk of transmission to the recipients may be considered. Guidelines and practices vary according to different countries.⁵⁸, ⁵⁹ However, any metastatic malignancy in the donor should exclude donation. Recipients of donors with malignancies should have their immunosuppression modulated because over immunosuppression reduces immune surveillance that can accelerate tumor growth. The potential benefit from mammalian target of rapamycin inhibitors (mTOR), which have both immunosuppressive and antiangiogenic properties,⁶⁰ requires investigation.

Donors with infection 

Infections carry an increased risk of transmission through organ donation and transplantation. If the causative organisms and antibiotic sensitivity patterns of most bacterial infections are known prior to organ donation, and if donors are partly treated, the risk of bacterial transmission and sepsis in the recipient is minimal.⁶¹ Meanwhile it is also difficult to estimate the real risk of bacterial sepsis in the recipient that is attributed to the organisms transmitted from the donor. However, there are exceptions to accepting organs from infected donors, as in case of active tuberculosis at the time of donation and a history of Creutzfeldt-Jakob disease. Severe systemic bacterial sepsis concomitant with abnormal liver function are an unfavorable combination, whereas other bacterial diseases, though rare, carry a risk of transmission and the resulting infection may also have implications on graft function (e.g., toxoplasmosis, syphilis).⁶² These grafts may be used with caution with appropriate post exposure antibiotic prophylaxis or treatment in the recipient.

Historically, human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) were considered absolute contraindications for organ donation.⁶³ Approximately 5% of people worldwide are chronically infected with hepatitis B. Overall, 15% of those chronically infected go on to develop cirrhosis, and an additional 20% will require LT. Acquisition of the HBV remains a concern after LT because the majority of the infections occur via transmission by the donor liver,⁶⁴ but some donors with past exposure to HBV infection can be used selectively in some recipients. The development of combined prophylaxis with hepatitis B immune globulin (HBIg) and lamivudine has proved effective not only against HBV recurrence but also against de novo HBV infection or transmission in recipients of anti-HBcAb + livers.⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸ Nery, et al,⁶⁸ reported that of 62 recipients of anti-HBc + livers, 60 were serologically free of HBV infection under combined or lamivudine monotherapy. These data suggest that the use of HBcAb + grafts is comparable with core antibody negative grafts and that survival was improved with dual immunoprophylaxis.⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹ In addition, Prieto, et al,⁷⁰ reported that post-transplantation HBV infection developed in 15 of 30 recipients of livers from anti-HBcAb + donors compared with 3 of 181 livers from anti-HBcAb — donors. Recipients of livers from anti-HBc + donors are at high risk for acquiring HBV infection, whereas recipients of livers from anti-HBs + donors are significantly less likely to acquire HBV infection, and this latter group may play a role in expanding the donor pool.⁷⁰

About 5% of all potential organ donors are positive for antibody to HCV,⁷¹ and the transplantation because of HCV cirrhosis has increased because of the greater prevalence of the virus in the last 15 years.⁷² Initially, the use of HCV + donor organs in LT was a source of great controversy and not commonly practiced. Underlying this practice was a concern for increased risk of aggressive viral recurrence in patients receiving HCV + grafts. LT for recipients with HCV cirrhosis from HCV + donors were found to provide graft survival that is equivalent to HCV–grafts to HCV + recipients.⁷³ Short-term studies in the early 1990s showed no difference in outcomes of HCV + grafts; increasing donor shortage allowed for the use of HCV + donor grafts in recipients with HCV to expand the donor pool. Long-term follow-up in the late 1990s confirmed that the use of grafts from HCV + donors is safe and that patient and graft survival are not affected.⁷⁴ Recurrence rates of hepatitis C, manifested by mild chronic hepatitis, fibrosis, or cirrhosis have been reported to be 54.55% in HCV + donor grafts when compared with 41.74% in HCV–grafts. Patient and graft survival at 4 years post-transplantation in HCV + donor grafts have been shown to be 83.9% and 71.9% versus 79.1% and 76.2%, respectively, in HCV–donor grafts.⁷⁵ Similar rates of HCV recurrence, patient survival, and graft survival have been reported by different centers using HCV + liver grafts for patients requiring transplantation for HCV cirrhosis.⁷⁴ Moreover, a report by Marroquin, et al,⁷⁴ showed that patient survival at two years was significantly higher in HCV + recipients of HCV + grafts than in HCV + recipients of HCV − grafts (90% versus 77%). In contrast, other studies indicated that in patients with HCV-related liver disease, there was no significant patient survival difference between the patients who received HCV + grafts and who received HCV − grafts.⁷⁵ However, caution should be used in selecting donors with active HCV infection or anti-HCV antibodies. Undetected fibrosis may lead to early graft failure and is also a predictor of HCV recurrence. Liver graft biopsy, histology activity index inflammatory grade and fibrosis scoring are helpful in decision-making.

There have been recent concerns over human T-lymphotropic virus (HTLV)-1 and HTLV-2 transmitted through transplanted and there is reluctance among the transplant community to accept grafts from such donors. It is worth emphasizing that in almost all such cases the donors are “screened” with a serological test.⁷⁶

Donation after cardiac death 

LT from non-heart-beating donors, now termed donation after cardiac death (DCD), is a promising way to increase the supply of organs.⁷⁷ In controlled circumstances, the organs are retrieved after a standoff period of 2–5 min after death is certified. In either controlled or uncontrolled DCD situations, the organs are subjected to a variable period of warm ischemia, which predisposes them to primary nonfunction, delayed graft function, or irreversible ischemic like diffuse cholangiopathy.⁷⁸ In early reports, the prolonged period of warm ischemia resulted in markedly increased early graft dysfunction in comparison with donation after brain death donors. Ischemic time has been shown to be extremely important when DCD is considered.⁷⁹ If warm ischemic time is restricted to <30 min and cold ischemia time <10 h, graft survival rate in the DCD group was found to be 81% and 67% at 1 and 3 years, respectively, which is not significantly different from recipients of dead-brain donors.⁸⁰ Results from uncontrolled DCD were less good, being graft survival at 2 years of 55%. The use of uncontrolled DCD livers was also associated with significantly higher incidence of PNF, DGF and biliary complications.¹⁸, ⁸⁰, ⁸¹, ⁸², ⁸³, ⁸⁴ It has been possible to achieve good results with an incidence of PNF below 15% and a lower incidence of biliary complications with specific measures (Table 1).⁸⁵, ⁸⁶ These measures include judicious donor selection, including donor age below 40 years and no steatosis, a specific resuscitation technique, including preservation of the organ with systemic heparin, the use of extra corporeal oxygenation, a short warm ischemia time (less than 15 min), and a short CIT (less than 10 h).⁸⁷, ⁸⁸ Although this procedure is limited to selected centers with specific protocols, DCD has the potential to increase the donor pool by 10%–20%.⁸⁹, ⁹⁰ Methods to address the microcirculation of the biliary system in DCD donors may improve the incidence of biliary strictures.⁴⁴

Hypernatremia

Hypernatremia has been shown to be one of the variables with prognostic value in predicting graft survival after transplantation in deceased donor liver transplant.⁹¹ Some studies have suggested that donors with hypernatremia can affect graft function and increase the risk of graft loss.⁹² The mechanism for the deleterious effect of elevated donor sodium on graft function is thought to be a result of cell swelling, increased osmolality and exacerbation of reperfusion-mediated injury.⁸³ The cause of hypernatremia could be related to derangement of fluid balance and diabetes insipidus in potential donors.⁹² In a study investigating the peak donor sodium level and the corrected sodium level at the time of retrieval, it was found that hypernatremia (sodium >155 mEq/L) was associated with 18.5% rate of PNF compared with 3.4% in eunatremic group. With the correction of hypernatremia before procurement, this rise in the PNF was no longer found.⁸³ Another pilot study at University of California examined the effects of infusing 5% dextrose in water through the inferior mesenteric vein before harvesting the organ if the donor sodium level was >160 mEq/L. In the 17 donors who received 5% dextrose to decrease hypernatremia, the rates of DGF/PNF were 0% compared with a group of historical controls that experienced a 60% incident of PNF/DGF.⁸³

Donors with hypotension and inotropic support 

Previous UNOS data have shown that donor organs subjected to prolonged hypotension have no significant increase in post-transplantation graft loss. However, graft loss was increased in liver transplant recipients when donors received norepinephrine.⁹² In other studies, dopamine dose >10 μg/kg/min⁹³ or 6 μg/kg/min⁸³ had a significant effect on early graft function. However, other factors such as age and fat content may modify these effects in either direction.

Briceño, et al,⁹² reported that unstable donors with high-doses of inotropic drugs have an increase in severe preservation damage rate, and trends to normalize hemodynamic status in dead-brain donors did not correct liver dysfunction. Probably, time-dependent administrations of high-dose dopamine and epinephrine have a harmful effect on liver function.

Split liver grafts 

In an attempt to expand the size of the donor pool, a number of surgical techniques have been developed over the past 15 years, including split liver transplant (SLT) and living donor liver transplant (LDLT).⁹⁴ Couinaud's⁹⁵ anatomical classification which was later refined by Bismuth,⁹⁶ permits the creation of partial liver grafts from either deceased or living donors. Surveys in Western populations indicate that SLT in adults is associated with significant increase (about 10%) in graft failure and recipient morbidity.⁸, ³³, ⁹⁷, ⁹⁸, ⁹⁹ Results are notably better in children.¹⁰⁰ Even if split liver grafts are procured from young donors with normal parenchyma and short CIT, they should be considered extended criteria grafts for the following reasons: (a) the graft volume is generally lower than the recipient's standard liver volume and may be insufficient to adequately meet the metabolic demand during the early postoperative course. (b) There are higher technical requirements, and nonoptimal positioning of the partial graft may result in compromised venous outflow. As a result, biliary leakage, hepatic artery thrombosis, focal or outflow obstruction, and poor early graft recovery are more frequent in comparison with whole organ transplantation.¹⁰¹ SLT for 2 adults has been performed in select transplant centers with better results for right allografts versus left allografts.¹⁰², ¹⁰³ Adult transplantation with a left graft remains a challenging technical procedure with a high risk of primary nonfunction due to insufficient parenchymal volume and often complex biliary and vascular anastomosis.¹⁰¹ Unless significant technical advances are achieved, the use of left allografts cannot be widely applied to adults but are best suited for pediatric recipients in whom SLT offers excellent results. In adults, SLT using the right lobe marginally increases the rate of graft failure. This should not represent a disincentive for using SLT, as this technique expands the donor pool, particularly for pediatric recipients.

Our experience 

We analyzed our initial results of extended criteria donors for DDLT.¹⁰⁴ A total of 33 patients were enrolled in this study. There were 20 marginal and 13 nonmarginal grafts. The two groups were well matched regarding age, sex and indication of liver transplantation, model for end-stage liver disease score, technique of transplant, requirement of vascular reconstruction, warm ischemia time, blood loss, mean operative time, etc (Table 2).

In our study, posttransplant peak level of liver enzymes, international normalization ratio, and bilirubin were not statistically significant in the marginal and nonmarginal group. Wound infection occurred in 10% of marginal compared with 7.7% of nonmarginal graft recipients (P > 0.05). In the marginal group, the incidences of vascular complications, hepatic artery thrombosis (four), and portal vein thrombosis (one) were not statistically significant compared to the nonmarginal group. Acute rejection was observed in a total of seven patients (21.2%)—five (25%) in the marginal group and two (15.4%) in the nonmarginal graft recipients. Primary nonfunction occurred in three (9.1%) patients—two (10%) in the marginal and one (7.7%) in the nonmarginal group. Average patient survival for the whole group was 91% at 1 week, 87.8% at 3 months, and 84.8% at 6 months (Table 3).

Ethical considerations and informed consent 

An ethical allocation practice is required based on justice, equity, and utility. Prospective recipients must be informed about the possibility of allograft-specific risks. They need to understand early in the transplant process (ideally at listing and without an allograft available) that donor risk is a continuum. Risk of graft failure and risk of disease transmission should also be emphasized as part of the informed consent process. Criteria for accepting and discarding extended criteria donors should be laid down in each transplant centre. A prospective evaluation necessitates that the donor characteristics and the outcome should be periodically reported in a standardized manner and centralized.

Future perspectives 

Use of normothermic regional perfusion (NRP) is under evolution. Principally, it is the amalgamation of two strategies to improve donor organ quality: Extra corporeal membrane oxygenation (ECMO) and in situ organ perfusion.¹⁰⁵ In the case of DCD organs it may be correct that if the inferior outcomes of DCD grafts are indeed due to initial donor warm ischemia times, these adverse insults can be counter acted by attempts to resuscitate organs (upon cardiac death) using ECMO.¹⁰⁶However, provided the cerebral circulation is isolated in the donor, the donor blood vessels provide the conduits for inflow and outflow to the ECMO circuit. In this sense it differs from ex situ perfusion, and organs are revived “in situ”. The evidence for success comes from Spain, where similar interventions have been employed in different organ donor settings where NRP has been successfully performed in the uncontrolled DCD setting.¹⁰⁷, ¹⁰⁸ As mentioned above, the practice of NRP is still in its infancy and none of the pioneering centers have yet published their results but the future of marginal DCD organ utility may rely on this novel intervention.

Conclusion

The issue of imbalance between the number of potential recipients of liver transplantation and available donors will not be resolved within the next few decades. So a number of patients with end-stage liver disease and/or liver malignancy will not considered for liver transplantation, although they could derive a significant benefit from this option. Therefore, in the absence of an efficient alternative to transplantation, the expansion of the donor pool will continue to be a priority. Moreover, ideal donors are often rare and most of the time the prospective donor has one or more adverse factors that make it an ECD. An ECD graft therefore should be regarded as an “otherwise unused” graft; hence it should benefit any recipient provided it is in favor of the recipient both in terms of survival and disease transmission. So-called ECD therefore have to be entertained to increase the graft utility rate. By employing a “utilitarian” approach, a significant number of organs from unconventional donors may be used. They may offer two benefits. Firstly, a utilitarian approach should be adopted to choose the best recipient to benefit from the particular graft in question, and secondly this may relax the competition in the transplant wait list.

Conflicts of interest 

All authors have none to declare.

References

Source

Probiotics Prevent Hepatic Encephalopathy in Patients With Cirrhosis: A Randomized Controlled Trial

Clin Gastroenterol Hepatol. 2013 Nov 15. pii: S1542-3565(13)01743-6. doi: 10.1016/j.cgh.2013.11.006. [Epub ahead of print]

Lunia MK¹, Sharma BC², Sharma P¹, Sachdeva S¹, Srivastava S¹.

Abstract

BACKGROUND & AIMS: Hepatic encephalopathy (HE) is associated with a poor prognosis in patients with advanced liver disease. Probiotics alter the intestinal microbiota with non-urease-producing organisms that reduce production of ammonia. We investigated the efficacy of probiotics for the primary prophylaxis of HE.

METHODS: We conducted a prospective trial at a tertiary care referral institute in New Delhi, India, from January 2012 through March 2013, of patients with cirrhosis without overt HE (age, 48.6 ± 11.1 y; 96 men and 64 women); 25 were Child-Turcotte-Pugh (CTP) class A, 51 were CTP class B, and 84 were CTP class C. Subjects were assigned randomly to groups given probiotics (1 × 10⁸ colony-forming units, 3 times daily; n = 86, 42 with minimal HE) or no test article (control, n = 74; 33 with minimal HE). All subjects underwent psychometric analyses, critical flicker fusion (CFF) threshold assessments, glucose hydrogen breath tests to identify small intestinal bacterial overgrowth (SIBO), and lactulose hydrogen breath tests to measure orocecal transit time (OCTT). The primary end point was the development of overt HE.

RESULTS: At baseline, subjects in each group had comparable CTP, model for end-stage liver disease scores, CFF assessments, psychometric hepatic encephalopathy scores, and OCTT. After a mean follow-up period of 38.6 ± 8.80 weeks for patients given probiotics and 40.3 ± 9.8 weeks for controls, 6 patients given probiotics and 7 controls died (P = .81). Three months of probiotic administration significantly reduced levels of arterial ammonia, SIBO, and OCTT; increased psychometric hepatic encephalopathy scores; and increased CFF thresholds, compared with baseline. Seven subjects in the probiotic group and 14 controls developed overt HE (P < .05; hazard ratio for controls vs probiotic group, 2.1; 95% confidence interval, 1.31-6.53). Psychometric hepatic encephalopathy scores, CTP scores, and SIBO correlated with the development of overt HE.

CONCLUSIONS: In a prospective, randomized controlled trial, probiotics were found to be effective in preventing HE in patients with cirrhosis. Trial registration no: CTRI/2012/07/002807.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS: ARR, CFF, CI, CTP, Child–Turcotte–Pugh, Clinical Trial, Cognitive Function, HE, MELD, MHE, Motor Function, NNT, OCTT, PHES, SIBO, Therapy, Treatment, absolute risk reduction, confidence interval, critical flicker frequency, hepatic encephalopathy, minimal hepatic encephalopathy, model for end stage liver disease, number needed to treat, orocecal transit time, psychometric hepatic encephalopathy score, small intestinal bacterial overgrowth

PMID: 24246768 [PubMed - as supplied by publisher]

Source

Measurement of the quality of care of patients admitted with decompensated cirrhosis

Liver International

Volume 34, Issue 2, pages 204–210, February 2014

Cirrhosis and Liver Failure

Rony Ghaoui^1,*, Jennifer Friderici², Paul Visintainer², Peter K. Lindenauer^3,4,5, Tara Lagu^3,4,5, David Desilets¹

Article first published online: 14 JUN 2013

DOI: 10.1111/liv.12225

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: decompensated cirrhosis; healthcare quality; outcome research

Abstract

Background & Aims

Process-based quality measures are increasingly used to evaluate hospital performance. However, practices vary, and patients with cirrhosis are a challenge to manage, given their risks of mortality, morbidity, and resources utilization. In 2010, process-based quality measures were developed to improve the care of these patients. We examined adherence with these quality measures for a cohort of patients admitted with decompensated cirrhosis in 2009.

Methods

We performed a retrospective analysis of all patients admitted to a tertiary-care hospital with decompensated cirrhosis in 2009 (n = 149 379) hospitalizations. Quality indicator (QI) scores were calculated for each admission as a fraction, i.e., the number of quality markers met divided by the number of possible quality indices, given the patient's presentation (range, 0–1). QI scores were correlated with patient characteristics and clinical outcomes (30-day readmission; inpatient death).

Results

Quality indicators were met 45% of the time (95% confidence interval, 40–51%). In multivariable analysis, QI scores were significantly lower among non-English-speaking patients and those who had congestive heart failure. QI scores were higher among patients with gastrointestinal bleeding or encephalopathy-related admission to the hospital. QI scores were not associated with inpatient mortality or 30-day readmission.

Conclusion

There is substantial opportunity to improve the care of patients hospitalized for decompensated cirrhosis. Additional research is needed to identify effective strategies for closing gaps in care. Adherence to quality measures did not affect clinical outcomes, but if easily measured in other settings could be used to compare hospitals and practices.

Source

Nestle To Study Brain and Liver Cells To Find Diet Disease Link

CBS/REUTERS January 8, 2014, 12: 22 PM

Nestle teams up with biotech to study how food affects human cells

Nestle is set to partner with biotechnology firm Cellular Dynamics International (CDI) to study the relation between diet and disease, according to a Wall Street Journal report.

The maker of Kit Kat chocolate bars and Maggi soups will take brain and liver cells from CDI to study the effect of nutrients found in foods, WSJ cited Emmanuel Baetge, director of the Nestle Institute of Health Sciences, saying in an interview.

Madison, Wisc.-based CDI develops and manufactures human cells in industrial quantities to precise specifications for research customers.

CDI said in a statement Wednesday it signed a long-term agreement to supply stem cells to the Nestle Institute of Health Sciences. Financial terms of the deal were not disclosed.

The Wall Street Journal added that Nestle scientists have already started studies of CDI nerve cells to see how the fatty acids found in avocados and olive oil affect them.

Nestle is increasingly linking up food and science with its health science unit, set up in 2011 to pursue a growing demand for "medical foods" from an aging population.

Last February, Nestle said it would buy U.S. company Pamlab, which makes such foods for patients with conditions including diabetic peripheral neuropathy, dementia, depression and high-risk pregnancy.

That deal followed the purchase in 2012 of a stake in U.S. firm Accera, which makes a medical food brand for Alzheimer's patients.

Experts expressed skepticism to the Journal that changing ingredients in foods may affect chronic diseases.

Marion Nestle, a professor of nutrition, food studies and public health at New York University, said adding nutrients to foods has never worked very well except for treating diseases caused by nutrient deficiencies.

Diseases "have multiple causes, and food is very complicated and diet is very complicated," said Nestle, who has no relationship to the food company.

Source

Nonalcoholic Fatty Liver Disease: Prevalence, Influence on Age and Sex, and Relationship with Metabolic Syndrome and Insulin Resistance

International Journal of Gerontology
Volume 7, Issue 4 , Pages 194-198, December 2013

Hui-Yun Cheng, Horng-Yuan Wang, Wen-Hsiung Chang, Shee-Chan Lin, Cheng-Hsin Chu, Tsang-En Wang, Chuan-Chuan Liu, Shou-Chuan Shih

Received 14 April 2012; received in revised form 20 August 2012; accepted 1 February 2013. published online 28 May 2013.

Summary

Background/purpose

Nonalcoholic fatty liver disease (NAFLD) is a common condition comprising a wide spectrum of liver damage strongly associated with type 2 diabetes, obesity, and hyperlipidemia. The pathogenesis of fatty liver is multifactorial, and it has been suggested that the presence of insulin resistance (IR) is an essential requirement for the accumulation of hepatocellular fat. Although NAFLD may affect people of any age, in general, increasing age is associated with increasing prevalence. The aim of this study was to determine the prevalence of fatty liver and its influence on age and sex; and to assess the association of different degrees of fatty liver to IR and metabolic syndrome.

Materials and methods

The study was performed in 8350 alcohol- and virus-negative individuals who underwent routine physical check-up at the health evaluation centre of Mackay Memorial Hospital, from February 2004 to May 2009. They underwent clinical examination, anthropometry, biochemical tests including serum fasting insulin, and routine liver ultrasonography. Steatosis was graded as absent, mild, moderate, or severe.

Results

The overall prevalence of fatty liver was 34.40% with the prevalence of fatty liver being significantly higher in males than in females (22.34 vs. 12.06%, p = 0.015). A progressive increase in the means of a homeostasis model assessment of IR (HOMA-IR), body mass index, systolic blood pressure, plasma triglyceride, alanine aminotransferase, low-density lipoprotein-cholesterol and glucose level and decrease in high-density lipoprotein-cholesterol (p < 0.001 and p < 0.05) was observed from the group without steatosis to the groups with mild, moderate, and severe steatosis. Severe steatosis was associated with the clustering of risk factors for metabolic syndrome. Individuals with metabolic syndrome and a more pronounced HOMA-IR had a higher prevalence of moderate to severe steatosis (p < 0.001 and p < 0.05) compared to those with HOMA-IR below the median.

Conclusion

Fatty liver can be considered as the hepatic consequence of metabolic syndrome, specifically IR. There is a high prevalence of metabolic syndrome and fatty liver among the elderly population. Metabolic disorders are closely related to fatty liver; moreover, fatty liver appears to be a good predictor for the clustering of risk factors for metabolic syndrome.

Keywords: hepatic metabolic syndrome, insulin resistance, nonalcoholic fatty liver disease

Source

Gender Differences in the Quality of Life of Patients with Liver Cirrhosis Related to Hepatitis C after Liver Transplantation

Blood Purification

Vol. 36, No. 3-4, 2013
Issue release date: Published online first

Free Access

Blood Purif 2013;36:231-236
(DOI:10.1159/000356362)

Bianco T.^d · Cillo U.^b · Amodio P.^c · Zanus G.^b · Salari A.^d · Neri D.^b ·Bombonato G.^c · Schiff S.^c · Baggio G.^a · Ronco C.^{e, f} · Brocca A.^{e, f} · Soni S.^f ·Minazzato L.^d

^aStudy Center of National Health and Gender Medicine, Padua Operating Unit, ^bUnit of Hepatobiliary Surgery, ^cDepartment of Clinical and Experimental Medicine, and^dAntalgic Therapy, Institute of Anesthesiology and Reanimation, University of Padua, Padua, ^eDepartment of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, and ^fInternational Renal Research Institute Vicenza (IRRIV), Vicenza, Italy

Key Words Gender differences, Hepatitis C, Liver transplantation, Pain perception, Quality of life, SF-36

Abstract

Background: Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, which adversely affects the quality of life (QoL) of the patient. The gender of the patient may be an important variable in the way severity of the disease is perceived. The aim of our study is to evaluate the effect of the gender variable on QoL in HCV-positive patients.Methods: This study included a total of 52 patients (26 men and 26 women) who completed a 1-year follow-up after liver transplantation. QoL was assessed using the SF-36 questionnaire. Results: Male subjects have significantly higher scores on physical role functioning, bodily pain and physical activity compared with females. Females have a better QoL compared to males with regard to the emotional state and mental health.Conclusions: These results show a significant effect of the gender variable on QoL in HCV patients.

© 2013 S. Karger AG, Basel

Introduction

The diagnosis of chronic liver disease has important implications on the patient's life, as it often marks the beginning of frequent medical checkups and treatment. It also involves the formalities related to enrolment into the liver transplant waiting list. In addition to the clinical effects of the liver disease, the psychological stress related to the continuous monitoring and assessments can affect health-related quality of life (HRQoL).

The World Health Organization (WHO) refers to ‘quality of life' as an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns [1]. In this sense, the HRQoL is defined as the set of physical, mental and social diseases assessed by somatic symptoms, psychological status and social interactions from the perspective of the patient, regardless of their medical condition. The international scientific community is increasingly interested in the QoL concept, particularly for the patients with chronic diseases. QoL studies can involve many different factors, ranging from the evaluation of the different effects of different diseases on daily activities and the identification of problems specific to each disease, to evaluate the effectiveness of different treatments and the specific factors that, in addition to patient compliance, determine treatment effectiveness.

In recent years, there have been numerous investigations on the QoL in patients with liver disease related to health, with particular attention to hepatitis C virus (HCV) positivity. This increased interest is justified by the significant spread of HCV in the world's population. In fact, the WHO estimated that worldwide there are about 140 million people affected by HCV, which corresponds to 2.2% of the global population. In Italy, about 2% of the general population is infected with HCV with a gradient that increases from north to south and the islands and with age (60% of patients with hepatitis) [2].

Even in the absence of overt liver disease, chronic HCV compromises HRQoL, with a negative impact on both mental health and physical well-being of the patient [3,4]. In fact, the vast majority of HCV patients present with nonspecific symptoms, such as fatigue, irritability, general malaise, abdominal pain, joint pain and headache [5]. In most cases, medical intervention is not required, however, physical and emotional health of the patient is affected. This in turn leads to inferior HRQoL for HCV patients [6]. Even if the patient is not aware of the seriousness of the disease, his psychological state is altered [7].

QoL in Patients with Liver Disease

Several studies seem to confirm a direct adverse effect of chronic HCV on HRQoL. Some recent reviews illustrate actual prospects of research in the field of QoL in patients with chronic liver disease. In a study from Britain, 72 unselected, consecutive patients with chronic HCV were compared with 30 consecutive patients with chronic hepatitis B infection and HBsAg positivity [4]. Patients with evidence of cirrhosis were excluded. SF-36 scores were markedly reduced in patients with chronic HCV infection, indicating that these patients perceived themselves as unwell and they reported a significant reduction in their QoL. Other researchers have shown that a significant percentage of HCV patients suffer from fatigue [8,9,10,11]. In one of the largest studies from France, Poynard et al. [12] reported that among 1,614 patients with HCV, 53% reported fatigue at their initial visit and the fatigue was severe in 17% of these patients. This study also found that fatigue was independently associated with female gender, age >50 years, cirrhosis, depression and purpura. In another study, HCV patients unaware of their HCV serostatus scored significantly worse in 3 parameters of general health, vitality and mental health [13]. Those aware of their serostatus did not differ demographically, clinically, virologically or serologically from those who were unaware, nor was there a link between QoL scores and objective measures of ill health. Numerous observations suggest that HCV may exert a direct effect on HRQoL through unknown mechanisms [14,15,16]. One possibility is that HCV may act within the central nervous system, since replicating viruses have been found within the nervous system tissue. Moreover, neuropsychiatric symptoms like fatigue, malaise, depression and cognitive impairment are among the most common complaints of patients with chronic hepatitis C and occur independently of liver disease or treatment status.

Importance of the Gender Variable

Over the past 30 years, medicine has reached incredible goals, including the description of the human genome, the ability to intervene at the beginning and end of life, the application of newest technologies for betterment of the patients, to name only a few. The achievements in many fields of medicine are based on evidence connected with guidelines. However, female gender has been inadequately represented in many of the epidemiological studies, which limits meaningful statistical analysis in many disorders.

The ‘woman question' emerged in 1991 when Bernadine Healy, the first female director of the National Institute of American Public Health, wrote a famous editorial in the New England Journal of Medicine [17]. She coined the term ‘Yentl syndrome' to highlight the gender-based disparities in the treatment and outcome of coronary artery disease in the intensive care unit (Yentl was a heroine of a Jewish story where a girl shaved her hair and disguised herself as a boy to enter religious training). Women in the intensive care unit were subjected to less diagnostic and therapeutic procedures than men and fewer invasive procedures such as cardiac catheterization and coronary artery bypass surgery [18,19]. Moreover, large prevention trials in patients with myocardial infarction did not include women at all. A clear discrimination by the cardiologists against the female patient was aptly emphasized. This editorial stirred basic researchers and clinicians around the world and was followed by a series of publications and studies designed to examine gender differences in various aspects of cardiovascular disease.

Another cornerstone of gender medicine was the Fourth World Conference on Women held in Peking in 1995, where the conviction to apply the principle of gender equality in all activities, including those for health, was considered a basic human right.

In 2002, the WHO established the Department for Gender and Women's Health to recognize the differences in disease burden and treatment between men and women. In 1999, the Italian Ministry for Equal Opportunities formally established a new group with the aim of working on gender disparities in medicine through a project entitled ‘A measure of health to a woman'. In 2001, a report on women's health was presented to the parliament and in 2003 a ‘Guide to women's health' was published. In Italy, the attention to the gender variable is now supported by the National Center for Health and Gender Medicine. The Center aims to gather information, impart training and encourage research in all fields of medicine. It also aims to network all Italian centers interested in these issues.

With regard to QoL in patients with chronic liver disease, the gender variable is not systematically studied so far. The aim of the present study is to assess the effect of the gender variable on the subjective evaluation of QoL in patients with chronic HCV infection.

Patients and Methods

SF-36 Questionnaire

SF-36 is the best-known, patient-oriented questionnaire for the assessment of one's general health condition. This test is the short form of the Medical Outcome Study questionnaire, which was developed by John Ware (the principal investigator) and his colleagues in the 1980s and was subject to successive modifications by researchers from various medical specialties [20]. The SF-36 is a generic instrument that proposes to evaluate the QoL from the patient's point of view. It is made up of 36 items divided into 8 scales (table 1) whose purpose is to evaluate the various aspects related to the patient's health and thereby furnish a global assessment of the patient's mental and physical well-being. To each question, a rough score is assigned; this initial score is further elaborated to furnish a final ranking only after evaluation of all answers given. The final response is given and the relationship between specific answers is evaluated to determine the score on each scale. Scoring on each scale is from 1 to 100, with higher values being indicative of a better-perceived QoL relative to one's health status (fig. 1). Scoring and standard deviations will vary from scale to scale and are also dependent on age. Its validity is recognized by the international community.

Table 1. Concepts of health according to the SF-36

Fig. 1. SF-36 scores in males and females. * p < 0.001.

Patients

This study included a total of 52 patients (26 men and 26 women) who completed a 1-year follow-up after liver transplantation. The HRQoL was assessed using the SF-36 questionnaire. The scores in the various domains of the questionnaire were compared using Student's t test. Analyses were performed using the statistical software SPSS 11.0.

Results

Male subjects have significantly higher scores on physical role functioning (daily activities or work is less impaired by physical health than in females), bodily pain (minor limitations due to pain) and physical activity (fewer constraints on the execution of physical activity in general) compared with females. On the other hand, females have a better QoL compared to males with regard to emotional role functioning (less impaired at emotional level) and mental health (self-satisfied and better mood stability).

Discussion

The way to deal with a disease and recovery will vary from person to person but there are gender differences that are often overlooked or incorrectly addressed. The significant difference between males and females with respect to ‘bodily pain' may be explained by the effects of various hormones on the body. Current research shows that estrogen would increase nervous system activity; this effect manifests itself in the increased transmission of pain stimuli and pain sensitivity of women. Conversely, testosterone has an analgesic effect and can reduce pain sensitivity in men [21]. Many previous studies dealing with behavioral responses evoked by nociceptive stimuli have demonstrated an increased sensitivity of females [22].

In our study, male patients scored higher in the category of ‘physical functioning' and ‘physical role functioning', which are the parameters related to physical activity and perceived limitations. The female patients scored less in both parameters, suggesting impaired QoL. This may partly be explained by the effect of ‘fatigue' in the posttransplant period. In an elegant cross-sectional study, van den Berg-Emons et al. [23] investigated the incidence, etiology, severity and factors of influence of fatigue in liver transplant recipients and concluded that the female gender perceives fatigue with greater severity.

In addition, sociocultural factors have to be considered. In fact, recent studies highlight the issue of gender difference in pain perception. It has been observed that for the same objective disease women report more pain than men [24]. These observations emphasize the fact that QoL assessment in liver transplant patients should not only include the clinical and biological condition of the patient but also psychosocial and cultural aspects. In this regard, it is also interesting to note that although female patients score less in the parameters ‘physical functioning' and ‘physical role functioning', they score better in the parameters of ‘emotional role functioning' and ‘mental health'. This highlights a better ability of females to manage stress and psychoemotional demands in the posttransplant setting. This could indicate differences in the ability of coping with stress between males and females of the study population.

Studies in the experience of pain in patriarchal ideology have highlighted ‘the central role of etiologic and coping strategies (‘being a good mother' to the female gender), suggesting that the patient needs pain to give meaning to their symptoms. It also helps to avoid negative feelings of despair and isolation. In this study, both males and females reported the common belief that a woman is better able to cope with painful events. This belief is also supported by the importance of the maternal role in women (experience of childbirth, breastfeeding, primary involvement in child rearing and emotional aspects of children) and explanations relating to the increased use of emotional expressiveness and the likelihood of seeking help and support of females. Recent studies have demonstrated sex differences in response to painful situations in teenagers and adolescents. It has been observed that males would mostly use distracting behavior while females make greater use of social support and positive self statements [25].

Studies on coping styles in the course of chronic diseases have shown that being active, thinking positively and expressing emotions positively correlated with significantly higher levels of functioning, with more positive scores in the clinical measures of disease and higher levels of psychological adjustment. The ability to adequately manage the transplant event and its consequences may foster greater satisfaction and improve QoL and HRQoL. In this sense, the gender differences in the QoL questionnaire identified in this study can help to direct attention to the most problematic and often neglected aspect for a patient undergoing a liver transplant by directing care and interventions in the posttransplant period in relation to an important variable such as gender.

Conclusion

HCV confers an inferior QoL to the patients. This effect is perceived by males and females in different ways.

References

1. Apolone G, Mosconi P, Ware JE Jr: Questionario sullo stato di salute SF-36. Manuale d'uso e guida all'interpretazione dei risultati. Milano, Guerini, 2000, vol 9, p 227.

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