Assessment of adult patients with chronic liver failure for liver transplantation in 2015: who and when?

In 2015, there are a few absolute contraindications to liver transplantation. In adult patients, survival post-liver transplant is excellent, with 1-year survival rate >90% and 5-year survival rates >80% and predicted median allograft survival beyond 20 years. Patients with a Child-Turcotte Pugh score ≥9 or a model for end-stage liver disease (MELD) score >15 should be referred for liver transplantation, with patients who have a MELD score >17 showing a 1-year survival benefit with liver transplantation. A careful selection of hepatocellular cancer patients results in excellent outcomes, while consideration of extra-hepatic disease (reversible vs irreversible) and social support structures are crucial to patient assessment. Alcoholic liver disease remains a challenge, and the potential to cure hepatitis C virus infection together with the emerging issue of non-alcoholic fatty liver disease-associated chronic liver failure will change the landscape of the who in the years ahead. The when will continue to be determined largely by the severity of liver disease based on the MELD score for the foreseeable future.

Suicidal emperipolesis: a process leading to cell-in-cell structures, T cell clearance and immune homeostasis.

"Suicidal emperipolesis" is one of the most recently reported processes leading to cell-in-cell structures that promote cell death. This process was discovered in studies investigating the fate of autoreactive CD8 T cells activated within the liver. Recently, we reported that activated T cells invaded hepatocytes, formed transient cell-in-cell structures, and were rapidly degraded within endosomal/lysosomal compartments by a non-apoptotic pathway. Importantly, pharmacological inhibition of this process caused intrahepatic accumulation of tissue-reactive T cells and breach of immune tolerance. The characterization of the molecular mechanisms of suicidal emperipolesis is still in its infancy, but initial studies suggest this phenomenon is distinct from other reported cell-in-cell structures. As opposed to the formation of other cell-in-cell structures, suicidal emperipolesis takes place in a non-malignant environment, and without obvious pathology. It is therefore the first cell-in-cell structure described to have a role in maintaining homeostasis in normal physiology in higher organisms. T cell emperipolesis within hepatocytes has also been observed by pathologists in a range of chronic human liver pathologies. As T cell-in-hepatocyte structures resulting from suicidal emperipolesis are very transiently observed in normal physiology, their accumulation during liver disease would suggest that severe tissue injury is promoted by, or associated with, defective T cell clearance. In this review, we compare "suicidal emperipolesis" to other processes leading to cell-in-cell structures, and consider its potential biological roles in maintaining immune homeostasis and tolerance in the context of the hepatic environment.

Antigen-specific primary activation of CD8+ T cells within the liver.

It is generally accepted that naive T cells recirculate via the blood and lymph, but do not enter nonlymphoid tissues without prior activation and differentiation. In this study, we demonstrate that the liver is an exception to this rule. Naive Des-TCR transgenic CD8(+) T cells specific for H-2K(b) were selectively retained in the liver within a few minutes of adoptive transfer into transgenic Met-K(b) mice expressing H-2K(b) in the liver. Activated CD8(+) cells were found in the liver, but not the blood, as soon as 2 h after transfer and underwent cell division and started to recirculate within 24 h of transfer. In contrast, CD8(+) cells activated in the lymph nodes remained sequestered at that site for 2 days before entering the blood. Our results therefore suggest that, in addition to its previously described role as a non Ag-specific activated T cell graveyard, the liver is involved in Ag-specific activation of naive recirculating CD8(+) T cells. This particular property of the liver, combined with the previously demonstrated ability of hepatocytes to induce tolerance by means of premature CD8(+) T cell death, may be a major mechanism contributing to the acceptance of liver allografts and the chronicity of viral hepatitis.

Posttransplant administration of donor leukocytes induces long-term acceptance of kidney or liver transplants by an activation-associated immune mechanism.

Donor leukocytes play a dual role in rejection and acceptance of transplanted organs. They provide the major stimulus for rejection, and their removal from the transplanted organ prolongs its survival. Paradoxically, administration of donor leukocytes also prolongs allograft survival provided that they are administered 1 wk or more before transplantation. Here we show that administration of donor leukocytes immediately after transplantation induced long-term acceptance of completely MHC-mismatched rat kidney or liver transplants. The majority of long-term recipients of kidney transplants were tolerant of donor-strain skin grafts. Acceptance was associated with early activation of recipient T cells in the spleen, demonstrated by a rapid increase in IL-2 and IFN-gamma at that site followed by an early diffuse infiltrate of activated T cells and apoptosis within the tolerant grafts. In contrast, IL-2 and IFN-gamma mRNA were not increased in the spleens of rejecting animals, and the diffuse infiltrate of activated T cells appeared later but resulted in rapid graft destruction. These results define a mechanism of allograft acceptance induced by donor leukocytes that is associated with activation-induced cell death of recipient T cells. They demonstrate for the first time that posttransplant administration of donor leukocytes leads to organ allograft tolerance across a complete MHC class I plus class II barrier, a finding with direct clinical application.

Use of 6-mercaptopurine in patients with inflammatory bowel disease previously intolerant of azathioprine.

Both azathioprine and its active metabolite, 6-mercaptopurine, are of benefit in the treatment of inflammatory bowel disease, either in resistant cases, or for their steroid-sparing effect. Azathioprine treatment is limited in some patients by hypersensitivity reactions or other side effects. We report our experience in 11 patients previously unable to tolerate azathioprine for a variety of reasons, who were switched to 6-mercaptopurine. Of seven patients with ulcerative colitis and four patients with Crohn's disease who were treated with 6-mercaptopurine following failed azathioprine therapy, six were able to successfully tolerate the substitute medication, with good response. Where patients have previously been intolerant of azathioprine yet ongoing indications for immunosuppressive therapy remain, a trial of 6-mercatopurine may be warranted. Given the similar efficacies of the two drugs in inflammatory bowel disease, these findings also favor the use of 6-mercaptopurine rather than the parent compound as initial therapy.

Molecular pathogenesis of liver disease: an approach to hepatic inflammation, cirrhosis and liver transplant tolerance.

The hallmarks of chronic liver diseases are chronic inflammation, cellular damage, regeneration and fibrosis. An appreciation of intrahepatic molecular expression patterns in normal and diseased liver provides clues for understanding pathogenic pathways whilst studies of the structure and function of molecules implicated in liver disease provide insights into their potential as therapeutic targets. We have examined the expression, function, molecular structure and structure-function relationships of type IV dipeptidyl aminopeptidases. In particular, the roles of CD26/DPPIV in T-cell proliferation and chemotaxis and of fibroblast activation protein in human cirrhosis are discussed. We have investigated the pathogenesis of liver disease by characterising patterns of cytokine and growth factor expression in experimental and human cirrhosis. We have quite recently expanded this approach to use differential gene expression analyses to elucidate overall pathways of gene activation and suppression in human cirrhosis. In addition, our detailed molecular and cellular studies of the mechanisms of spontaneous liver transplant tolerance have generated novel insights into this process. This review touches on these diverse aspects of liver function and disease.

Evidence that apoptosis of activated T cells occurs in spontaneous tolerance of liver allografts and is blocked by manipulations which break tolerance.

BACKGROUND: Fully allogeneic liver grafts from piebald virol glaxo to dark agouti rats are spontaneously tolerated, whereas kidney transplants between these strains are rejected. Liver tolerance is broken by donor irradiation or peritransplant corticosteroid treatment of recipient rats, both of which interfere with the activation of recipient cells. METHODS: In this study we used a combination of immunohistochemical staining, reverse transcription-polymerase chain reaction, and terminal deoxynucleotide transferase-mediated dUTP nick end labeling and Annexin-V apoptosis assays to compare donor cell migration, cytokine profiles, and leukocyte apoptosis in grafts and lymphoid organs from tolerant liver and rejecting kidney recipients. We then examined the effect on apoptosis of treatments which abrogate liver tolerance. RESULTS: Liver transplantation in this tolerant strain combination is accompanied by rapid migration of many passenger leukocytes to the recipient spleen and lymph node, concurrent with a marked but transient increase in the amount of mRNA for the cytokines interleukin-2 and interferon-gamma. Apoptotic cells appear promptly in the spleen, their numbers reaching a peak 2 days earlier than has been previously shown for the graft infiltrate. Both CD4+ and CD8+ T cells undergo apoptosis and apoptotic cells are most concentrated among CD25+ T cells. In contrast, renal transplant rejection is associated with limited donor cell migration to lymphoid tissues and significantly less up-regulation of interleukin-2 and interferon-gamma in the spleen. Few apoptotic cells are detected in spleen or graft infiltrate during rejection, whereas apoptotic renal tubular and glomerular cells are found from day 5. Either recipient steroid treatment or donor irradiation significantly reduced the number of apoptotic cells in liver graft infiltrates and recipient spleen. CONCLUSIONS: Taken together, these findings suggest that a mechanism akin to activation-induced cell death, with apoptosis of alloreactive recipient cells may be responsible for the induction of spontaneous liver transplant tolerance.

Breast reconstruction in a male with a transverse rectus abdominis flap.

The TRAM flap may be the best choice in male breast reconstruction not just because it can replace the missing skin and fat but also because it may be a source of hair-bearing skin similar to the native breast skin.

Video push enteroscopy in the investigation of small bowel disease: defining clinical indications and outcomes.

BACKGROUND: Push enteroscopy is a new technique for investigation of the small intestine. The clinical indications are still being defined. It also offers the potential for therapeutic intervention in suitable cases. AIMS: To evaluate further the role of push enteroscopy in the diagnosis and treatment of patients with suspected or known small bowel disease. METHODS: A prospective record was kept of all patients having enteroscopy at Royal Prince Alfred Hospital between March 1995 and July 1997. The procedure was performed 73 times in 68 patients. Indications and diagnoses were noted. The outcome in patients with obscure gastrointestinal bleeding or anaemia in whom a vascular lesion was treated with a heater probe was also determined. RESULTS: Enteroscopy was performed in 23 patients for gastrointestinal bleeding of obscure origin. An active or possible bleeding source was found in 13 (57%). The commonest of these was jejunal angiodysplasia. In the 21 patients with chronic iron deficiency anaemia a lesion was found in ten (48%). The majority of these were in the stomach, as described by others. The diagnostic yield in the 16 patients having enteroscopy for known or suspected small bowel disease was 56%. One patient underwent balloon dilatation of a postoperative jejunal stricture. Eleven patients with obscure bleeding or anaemia had ablation of a vascular lesion with a heater probe. Transfusion requirements fell after this procedure, particularly in those with active bleeding at the time of the examination. In five of the 11 no further transfusions were required in over six months of follow-up. CONCLUSIONS: The most common indications for enteroscopy are obscure gastrointestinal bleeding, chronic anaemia and known or suspected small bowel disease. A positive result can be expected in over 50% of patients. The treatment of vascular lesions via the enteroscope has a significant impact of subsequent transfusion requirements.

Secondary surgery and silicone implants: one center's experience before and after the food and drug administration hearings of 1991 and 1992.

LEARNING OBJECTIVES: The reader is presumed to have a broad understanding of plastic surgical procedures and concepts. After studying this article, the participant should be able to: Physicians may earn 1 hour of Category 1 CME credit by successfully completing the examination based on material covered in this article. The examination begins on page 175. A retrospective study was performed to compare reoperative breast implantation surgery before and after the Food and Drug Administration (FDA) hearings in 1991 and 1992 on silicone breast implants. The two groups were compared regarding the motivation, findings, and procedures associated with the operations. One hundred seventy-one patient records were reviewed covering the years 1989 to 1994, evenly straddling 1991; of those, 146 charts had sufficient data to be included in the study. Each implant and each implantation operation were counted as a separate event. Before November 1991, 64% of reoperations were performed on the senior author's own original patients, whereas after 1991, only 33% were. Fifty-seven percent of the reoperations performed before November 1991 were performed on patients requiring augmentation in contrast to those patients requiring reconstruction; after 1991, 78% of the reoperations were augmentation mammaplasties. In the early period, reoperation was primarily performed to correct asymmetry (47%) or capsular contracture (47%); it was rarely performed for rupture (3%) or infection (3%) and never for anxiety or pain. In the later period, contracture (44%) and asymmetry (18%) remained as common causes, but anxiety (11%) and pain (8%) appeared as new factors, and rupture was suspected more often (21%). One of the most dramatic, if not surprising, findings was the choice for replacement implant. In the earlier period, saline solution-filled implants were used 12% of the time, whereas in the later period, they were used 80% of the time. Finally, implants removed that were more than 15 years old had ruptured nearly 50% of the time.

Delayed development of an ectopic frontal sinus mucocele after pediatric cranial trauma.

We describe the delayed occurrence of a frontal sinus mucocele 14 years after the original trauma. The patient presented with a laterally displaced, enlarging mass that encroached on the dura. The sterile mucocele was removed, and the cranial defect was reconstructed with methyl methacrylate and wire mesh. Our experience confirms the known but rarely observed late development of a mucocele after pediatric facial trauma. To prevent the sequela of mucocele development, the mucosa of the rudimentary frontal sinus in the pediatric patient must be carefully sought and ablated during reconstructive procedures of the forehead when traumatic injury significantly disrupts the normal bony anatomy.

Seroprevalence of human immunodeficiency virus in admitted trauma patients at a southeastern metropolitan/rural trauma center.

Human Immunodeficiency Virus (HIV) seropositivity was prospectively evaluated for trauma patients admitted to Memorial Medical Center between September 1989 and August 1990. Epidemiologic data, HIV risk factors, and opportunity for body fluid exposure were compiled for 520 admitted trauma patients 15 years of age or older who met inclusion criteria. Serum samples were obtained from initial laboratory tests. Patient identifiers were removed, and matching blinded numbers were placed on patient serum and data forms. Centers for Disease Control laboratories tested for HIV with the enzyme-linked immunosorbent assay method. The Epi-Info (Version 5.01, 1990) software package was used for statistical analysis of epidemiologic data. Results showed HIV seropositivity of admitted trauma patients to be 0.96 per cent (5/520). HIV seroprevalence among young black males from our urban area who were injured during violent aggression was 3.5 per cent. Management of 80 per cent of patients resulted in opportunity for body fluid exposure. Illicit drug use was reported by 15 per cent; 7.5 per cent gave a history of transfusion since 1977; 3 per cent identified high risk sexual partners; three patients reported homosexual activity. Two patients denied risk factors, but were HIV-seropositive. The results indicate that HIV exposure is a potential hazard to health care workers and that HIV risk factors alone are not reliable in identifying the HIV-positive patient.

A five-year retrospective study of admissions to a trauma center in southeast Georgia.

A five-year retrospective review of a computerized trauma registry at Memorial Medical Center, Inc. (MMC), the designated Level I Trauma Center of Region IX EMS, was accomplished to identify patterns of epidemiology and use of our regional trauma center. All trauma admissions from 1983 through 1987 were reviewed with respect to mechanism of injury, age, gender, outcome, mode of prehospital transport, and referral source. Seventy-five percent of 4862 admissions were due to blunt trauma. Sixty percent were brought directly to the trauma center; 40% were interhospital transfers from outside the local area. The average length of stay was 12 days. Retrospective review of trauma registry data is helpful in determining the use and quality of care of a regional trauma center.