The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Combined liver transplantation and gastric sleeve resection for patients with medically complicated obesity and end-stage liver disease.

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. Our aim was to analyze the effectiveness of a multidisciplinary protocol for obese patients requiring LT, including a noninvasive pretransplant weight loss program, and a combined LT plus sleeve gastrectomy (SG) for obese patients who failed to lose weight prior to LT. Since 2006, all patients referred LT with a BMI > 35 were enrolled. There were 37 patients who achieved weight loss and underwent LT alone, and 7 who underwent LT combined with SG. In those who received LT alone, weight gain to BMI > 35 was seen in 21/34, post-LT diabetes (DM) in 12/34, steatosis in 7/34, with 3 deaths plus 3 grafts losses. In patients undergoing the combined procedure, there were no deaths or graft losses. One patient developed a leak from the gastric staple line, and one had excess weight loss. No patients developed post-LT DM or steatosis, and all had substantial weight loss (mean BMI = 29). Noninvasive pretransplant weight loss was achieved by a majority, though weight gain post-LT was common. Combined LT plus SG resulted in effective weight loss and was associated with fewer post-LT metabolic complications. Long-term follow-up is needed.

Insulin resistance, serum adipokines and risk of fibrosis progression in patients transplanted for hepatitis C.

In the nontransplant setting diabetes mellitus is a risk factor for disease progression in patients with chronic hepatitis C virus (HCV) infection. The impact of early insulin resistance on the development of advanced fibrosis, even in the absence of clinically apparent diabetes mellitus, is not known. Our aim was to determine whether the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) can be used to identify insulin-resistant patients at risk for rapid fibrosis progression. Cohort study including patients transplanted for chronic HCV between January 1, 1995 and January 1, 2005. One hundred sixty patients were included; 25 patients (16%) were treated for diabetes mellitus and 36 patients (23%) were prediabetic, defined as HOMA-IR >2.5. Multivariate Cox regression analysis showed that insulin resistance (hazard ratio (HR) 2.07; confidence interval (CI) 1.10-3.91, p = 0.024), donor age (HR 1.33;CI 1.08-1.63, p = 0.007) and aspartate aminotransferase (HR 1.03;CI 1.01-1.05, p < 0.001) were significantly associated with a higher probability of developing advanced fibrosis, i.e. Knodell fibrosis stage 3 or 4, whereas steatosis (HR 0.94;CI 0.46-1.92, p = 0.87) and acute cellular rejection (HR 1.72;CI 0.88-3.36, p = 0.111) were not. In conclusion, posttransplant insulin resistance is strongly associated with more severe recurrence of HCV infection. HOMA-IR is an important tool for the identification of insulin resistance among patients at risk for rapid fibrosis progression after liver transplantation for HCV.

Impact of pegylated interferon and ribavirin treatment on graft survival in liver transplant patients with recurrent hepatitis C infection.

Recurrent hepatitis C virus (HCV) infection is a major cause of morbidity and mortality after liver transplantation for HCV-related end stage liver disease. Although previous studies have shown a short-term effect of interferon-based treatment on fibrosis progression, it is unclear whether this translates to improved graft survival. We evaluated whether treatment of recurrent HCV leads to an improved graft survival. Cohort study included consecutive HCV patients who underwent liver transplantation between 1 January 1995 and 1 January 2005 in the Mayo Clinic, Rochester, MN. Two hundred and fifteen patients were included in the study. During a median follow-up of 4.4 years (interquartile range 2.2-6.6), 165 patients (77%) had biopsy-proven recurrent HCV infection confirmed by serum HCV RNA testing. Seventy-eight patients were treated. There were no differences in MELD-score, fibrosis stage or time towards HCV recurrence between treated and untreated patients at time of recurrence. There was a trend for greater frequency of acute cellular rejection among untreated patients. The incidence of graft failure was lower for patients treated within 6 months of recurrence compared to patients not treated within this time-period (log rank p = 0.002). Time-dependent multivariate Cox regression analysis showed that treatment of recurrent HCV infection was statistically significantly associated with a decreased risk of overall graft failure (hazard ratio 0.34; CI 0.15-0.77, p = 0.009) and a decreased risk of graft failure due to recurrent HCV (hazard ratio 0.24; CI 0.08-0.69, p = 0.008). In conclusion, although a cause and effect relationship cannot be established, treatment of recurrent HCV infection after liver transplantation is associated with a reduced risk of graft failure.

Use of fatty donor liver is associated with diminished early patient and graft survival.

It is well known that implantation of donor livers with severe fatty infiltration (>60%) is frequently associated with early hepatic dysfunction and an increased incidence of primary nonfunction after liver transplantation. The outcome of donor livers with less fatty infiltration has not been well defined. We, therefore, studied the outcome of 59 liver transplantations in which donor livers with up to 30% fat were used. Patient outcome was compared to a time-matched control group of 57 patients. The two groups were similar in terms of age, gender, preservation time, primary diagnosis, and UNOS status. We compared both groups with regard to 4-month and 2-year patient and graft survival. We also assessed the incidence of ischemic type biliary strictures and hepatic artery thrombosis, and evaluated the causes of graft loss in both groups. We found that use of donor livers with up to 30% fatty infiltration was associated with a significant decrease in 4-month graft survival (76% vs. 89%, P<0.05) and in 2-year patient survival (77% vs. 91%, P<0.05). Primary nonfunction and primary dysfunction formed the main cause of graft loss and mortality. Multivariate analysis showed that fatty infiltration is an independent predictive factor for outcome after transplantation. We conclude that liver allografts with up to 30% fat lead to diminished outcome after liver transplantation. However, this diminished outcome should be viewed with respect to the increasing mortality on the national waiting list.

Osteoporosis.

Osteopenia, in the form of osteoporosis, is a common complication of chronic cholestatic liver diseases and, although its cause is poorly understood, it appears to be intimately related to the cholestasis itself. With more patients surviving longer with successful liver transplantation, the clinical significance of such osteopenia has increased, and a traumatic fracturing has become a major cause of morbidity in this patient population. Noninvasive diagnosis is easy, and serial measurements allow assessment of disease progression. Although no effective therapy can treat or prevent this complication, supportive measures can improve skeletal well-being, especially in high-risk individuals who are candidates for liver transplantation.

Clinical features and prognostic implications of severe corticosteroid-treated cryptogenic chronic active hepatitis.

To assess the nature and prognosis of severe chronic active hepatitis of unknown cause, we compared 26 patients who had been fully screened for etiologic factors with 112 patients who had autoimmune chronic active hepatitis after similar durations of corticosteroid therapy (17(+)/- 2 versus 23 (+)/- 2 months), and follow-up versus 103 +/- 7 months). Patients with cryptogenic disease could not be distinguished from those with autoimmune disease on the basis of age, sex distribution, duration of illness, immunoglobulin levels, frequency of concurrent immunologic disorders, or histologic findings. Serum gamma-globulin levels were higher (3.4 +/- 0.1 versus 2.5 +/- 0.2 g/dl, P = 0.007) and albumin levels were lower (2.9 +/- 0.1 versus 3.3 +/- 0.1 g/dl, P = 0.003) in patients with autoimmune disease than in those with cryptogenic disease, but individual findings did not differentiate the patients. Remission (69 versus 75%), treatment failure (23 versus 13%), relapse after drug withdrawal (67 versus 68%), progression to cirrhosis (57 versus 36%), and death from hepatic failure (12 versus 11%) occurred as commonly in patients with cryptogenic as in those with autoimmune disease. Patients with different constellations of immunoserologic findings were similar clinically. We conclude that patients with severe chronic active hepatitis who have been fully screened for etiologic factors cannot be distinguished from patients with autoimmune disease of comparable severity. These two groups of patients have a similar prognosis after corticosteroid therapy, and such treatment should be considered in these highly selected patients.

Hepatic allograft rejection: new developments in terminology, diagnosis, prevention, and treatment.

Hepatic allograft rejection remains a major cause of morbidity related to the need for increased immunosuppression and continues to be a principal cause of late failure of the graft. Hepatic allograft rejection is defined on the basis of morphologic findings; cellular rejection is defined as portal or periportal hepatitis with nonsuppurative cholangitis or endotheliitis (or both), and ductopenic rejection is defined as loss of interlobular and septal bile ducts, typically in at least 50% of the portal tracts. The overall incidence of episodes of cellular rejection, which usually occur within the first 2 weeks after liver transplantation, varies from 50 to 100%. Ductopenic rejection occurs in approximately 8% of patients who undergo initial liver transplantation and is usually diagnosed between 6 weeks and 6 months after transplantation. Induction and maintenance immunosuppression with triple-drug (cyclosporine, prednisone, and azathioprine) therapy and other combinations that include antilymphocyte preparations, however, has decreased the incidence of both cellular and ductopenic rejection. In patients experiencing episodes of cellular rejection, high-dose intravenously administered corticosteroid therapy yields the best response and is associated with a lower incidence of ductopenic rejection than is low-dose and orally administered corticosteroid therapy. The correlation between degree of biochemical liver dysfunction and presence of histologic rejection is minimal early after transplantation. Histologic severity of rejection, however, suggests which patients will require more immunosuppression and which patients may need antilymphocyte therapy for controlling the rejection episode. With the availability of new immunosuppressive agents, distinguishing patients at high risk for rejection is important. The goals for use of new immunosuppressive agents and regimens are to improve graft and patient survival, to decrease the incidence of cellular and ductopenic rejection, and to minimize side effects and complications.

Orthotopic liver transplantation for preoperative early-stage hepatocellular carcinoma.

OBJECTIVE: To report our experience with orthotopic liver transplantation (OLT) for highly selected patients with early-stage hepatocellular carcinoma (HCC). DESIGN: We retrospectively analyzed the demographic, clinical, pathologic, and survival data on 21 patients with HCC who underwent OLT at the Mayo Clinic between 1985 and 1993. MATERIAL AND METHODS: The 21 patients were categorized into three groups: (1) those with incidental HCC (no evidence of HCC preoperatively), (2) those with a unicentric hepatic lesion without vascular invasion, and (3) those with an increased serum alpha-fetoprotein (AFP) concentration but no detectable mass lesion in the liver. RESULTS: For the seven patients with incidental HCC, the 2-year disease-free survival was 68.5%. For the eight patients with a mass lesion, the 2-year disease-free survival was only 50%. Operative staging revealed more advanced stage disease than had been found on preoperative assessment in five of these eight patients. For the six patients with an increased serum AFP value but no mass lesion, the 2-year disease-free survival was 80%. Tumor recurrence was the major cause of all deaths in this series. CONCLUSION: Disease-free survival for patients with radiographic early-stage HCC was suboptimal because of understaging of the disease preoperatively. In contrast, our initial experience with OLT for patients with an increased serum AFP value in the absence of a mass lesion in the liver was favorable.

Nephrotoxic effects of primary immunosuppression with FK-506 and cyclosporine regimens after liver transplantation.

OBJECTIVE: We conducted a treatment trial to determine the relative toxicity of FK-506 and cyclosporine A (CSA) in liver transplant recipients. DESIGN: Between October 1990 and October 1991, 37 patients were enrolled in an open-labeled, randomized study of two immunosuppressive regimens after liver transplantation. MATERIAL AND METHODS: Of the 23 men and 14 women, 20 received FK-506 plus prednisone, and 17 received CSA plus prednisone and azathioprine. Renal function was assessed before and after transplantation (day 1, month 1, month 4, and month 12) by measurements of serum creatinine (SCr) and glomerular filtration rate (GFR) as determined by urinary iothalamate or creatinine clearance (or both). FK-506 trough plasma levels (enzyme immunoassay) were to be maintained between 0.2 and 5.0 ng/mL, and CSA trough blood levels (whole blood high-performance liquid chromatography) were to be maintained between 250 and 400 ng/mL. Severe nephrotoxicity was defined as sudden decreases in urine output to less than 10 mL/h or rapid increases in SCr (more than 0.5 mg/dL daily) that necessitated withdrawal of study medication for more than 48 hours. Mean patient age and values for SCr and GFR were comparable between the two groups at entry. RESULTS: Both study groups demonstrated a similar deterioration in renal function during a 12-month follow-up, although patients who received FK-506 had a significantly (P < 0.05) lower GFR when measured at 12 months than did patients treated with CSA (45 +/- 4 versus 64 +/- 6 mL/min per body surface area). Mild nephrotoxicity that responded to decreased drug doses was noted in 9 CSA-treated patients (53%) and 10 FK-506-treated patients (50%). Severe nephrotoxicity that necessitated drug withdrawal occurred in only four patients, all of whom were in the FK-506 group. These severe nephrotoxic reactions to FK-506 occurred early after transplantation, often during intravenous administration of the drug, and were not associated with poor liver allograft function or drug levels outside the therapeutic range. CONCLUSION: Both FK-506 and CSA are significantly nephrotoxic in liver transplant recipients. In this trial, however, we observed an early development of severe nephrotoxic reactions only in some patients who received FK-506.

Auditory and inspiratory gasp-evoked sympathetic skin response: age effects.

The sympathetic skin response (SSR) has been employed to assess peripheral neuropathy as an index of sympathetic sudomotor activity. A variety of stimuli can be used to elicit the SSR, but their relative ease of use and reliability have not been studied. In addition, the extent to which age affects the SSR remains unresolved. We compared two different stimuli, a sudden loud noise and an inspiratory gasp, whilst recording SSRs from the hand and foot. We also investigated the effects of age on SSR amplitude and latency in 58 healthy volunteers (ages 13-79). SSRs evoked by the auditory stimulus were recorded in all subjects, while gasp-induced SSRs were not elicited in two subjects. We found that SSRs evoked by the auditory stimulus had less inter- and intra-subject latency and waveform variability than the gasp-induced response. The increased latency variability associated with the inspiratory gasp technique was probably due to triggering errors. Our results confirmed that the amplitude of the SSR is extremely variable and appears to be affected by many factors. Auditory-evoked SSR latencies revealed a significant non-linear increase with age, while SSRs evoked by an inspiratory gasp did not demonstrate age dependence. We conclude that an auditory stimulus is superior to an inspiratory gasp in evoking SSRs, both in terms of consistent appearance and reduced latency variability. As the SSR latency increases significantly with age, this effect should be carefully considered when interpreting the response.

Review article: the management of cirrhosis in women.

BACKGROUND: There are differences in the predisposition, natural history of liver disease, complications and treatment response between men and women. AIM: To review clinical differences in cirrhosis between men and women and to address unique management issues of fertility, pregnancy and contraception in this patient population. METHODS: PubMed and MEDLINE were searched using the terms 'cirrhosis' and 'chronic liver disease', each cross-referenced with specific liver diseases, as well as terms such as 'cancer', 'hepatocellular carcinoma', 'smoking', 'liver transplantation', 'metabolic bone disease', 'fertility',' pregnancy' and 'contraception'. RESULTS: Pre-menopausal status is protective in viral hepatitis C and non-alcoholic steatohepatitis. However, smoking, especially in combination with alcohol, is a stronger risk factor for cirrhosis and malignancies in women with chronic liver disease compared to men, although they are less likely than men to develop hepatocellular carcinoma. Women with cirrhosis have more osteopenic bone disease than men and require active management. Successful pregnancy is possible in well-compensated cirrhosis or with mild portal hypertension, although the maternal and foetal mortality and morbidity are higher than in the general population. The maternal risk correlates with liver disease severity and derives mostly from variceal bleeding. The choices for contraception in compensated cirrhosis are generally the same as for the general population. Women with cirrhosis are disadvantaged by the current MELD system of organ allocation, at least in part due to body size. CONCLUSION: The management of women with chronic liver disease is unique in regards to counselling, screening for complications, fertility and pregnancy.

Bone disease in liver transplant recipients.

Osteopenic bone disease with atraumatic fracturing is a major cause of morbidity in liver transplant recipients. The course of bone loss after transplantation is biphasic, consisting of an early phase with acute loss of bone followed by stabilization or even improvement in bone density. The pathophysiology of the osteopenia is poorly understood, and treatment is supportive. Osteonecrosis is a second, less common skeletal complication after liver transplantation, assumed to be related to the use of corticosteroids.