Clark A. Bonham

Treatment of Methylmalonic Acidemia by Liver or Combined Liver-Kidney Transplantation

OBJECTIVE To assess biochemical, surgical, and long-term outcomes of liver (LT) or liver-kidney transplantation (LKT) for severe, early-onset methylmalonic acidemia/acid (MMA). STUDY DESIGN A retrospective chart review (December 1997 to May 2012) of patients with MMA who underwent LT or LKT at Lucile Packard Childrens Hospital at Stanford. RESULTS Fourteen patients underwent LT (n = 6) or LKT (n = 8) at mean age 8.2 years (range 0.8-20.7). Eleven (79%) were diagnosed during the neonatal period, including 6 by newborn screening. All underwent deceased donor transplantation; 12 (86%) received a whole liver graft. Postoperative survival was 100%. At a mean follow-up of 3.25 ± 4.2 years, patient survival was 100%, liver allograft survival 93%, and kidney allograft survival 100%. One patient underwent liver re-transplantation because of hepatic artery thrombosis. After transplantation, there were no episodes of hyperammonemia, acidosis, or metabolic decompensation. The mean serum MMA at the time of transplantation was 1648 ± 1492 μmol/L (normal <0.3, range 99-4420). By 3 days, post-transplantation levels fell on average by 87% (mean 210 ± 154 μmol/L), and at 4 months, they were 83% below pre-transplantation levels (mean 305 ± 108 μmol/L). Developmental delay was present in 12 patients (86%) before transplantation. All patients maintained neurodevelopmental abilities or exhibited improvements in motor skills, learning abilities, and social functioning. CONCLUSIONS LT or LKT for MMA eradicates episodes of hyperammonemia, results in excellent long-term survival, and suggests stabilization of neurocognitive development. Long-term follow-up is underway to evaluate whether patients who undergo early LT need kidney transplantation later in life.

Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002-2012 United Network for Organ Sharing data.

There is an increasing trend of patients with hepatocellular carcinoma (HCC) and non‐alcoholic fatty liver disease undergoing liver transplantation in the US. Our study utilized data from the 2002 to 2012 United Network for Organ Sharing registry to evaluate model for end‐stage liver disease era trends in US liver transplantations focused on patients with non‐alcoholic steatohepatitis (NASH), hepatitis C (HCV), alcoholic liver disease (ALD), and HCC. Survival outcomes were stratified by liver disease etiology and compared across time periods using Kaplan–Meier and Cox proportional hazards models. Patients with NASH were more likely to be women, had higher body mass index (BMI), and had higher prevalence of diabetes and cardiac disease. However, overall long‐term survival was significantly higher in patients with NASH and ALD (p < 0.001). Compared to HCV, patients with NASH had significantly higher post‐transplantation survival (HR 0.69, 95% CI 0.63–0.77), and lower risk of graft failure (HR 0.76, 95% CI 0.69–0.83). Despite having higher BMI and higher prevalence of diabetes and cardiac disease, patients with NASH had better post‐liver transplantation survival compared to patients with HCV or HCC. Patients with ALD also had superior survival outcomes. However, these survival differences were limited to patients without HCC that underwent liver transplantation.

Liver transplantation for urea cycle disorders in pediatric patients: A single-center experience

LT has emerged as a surgical treatment for UCDs. We hypothesize that LT can be safely and broadly utilized in the pediatric population to effectively prevent hyperammonemic crises and potentially improve neurocognitive outcomes. To determine the long‐term outcomes of LT for UCDs, charts of children with UCD who underwent LT were retrospectively reviewed at an academic institution between July 2001 and May 2012. A total of 23 patients with UCD underwent LT at a mean age of 3.4 yr. Fifteen (65%) patients received a whole‐liver graft, seven patients (30%) received a reduced‐size graft, and one patient received a living donor graft. Mean five‐yr patient survival was 100%, and allograft survival was 96%. Mean peak blood ammonia (NH3) at presentation was 772 μmol/L (median 500, range 178–2969, normal <30–50). After transplantation, there were no episodes of hyperammonemia. Eleven patients were diagnosed with some degree of developmental delay before transplantation, which remained stable or improved after transplantation. Patients without developmental delay before transplantation maintained their cognitive abilities at long‐term follow‐up. LT was associated with the eradication of hyperammonemia, removal of dietary restrictions, and potentially improved neurocognitive development. Long‐term follow‐up is underway to evaluate whether LT at an early age (<1 yr) will attain improved neurodevelopmental outcomes.

Pediatric combined heart-liver transplantation performed en bloc: a single-center experience.

Hill AL, Maeda K, Bonham CA, Concepcion W. Pediatric combined heart–liver transplantation performed en bloc: A single‐center experience.

Portal venous remodeling after endovascular reduction of pediatric autogenous portosystemic shunts.

Patients with autogenous native vessel portosystemic shunts, whether surgical or congenital, may experience complications of excess shunt flow, including hepatopulmonary syndrome (HPS), hepatic encephalopathy (HE), and hepatic insufficiency. The authors explored endovascular reduction or occlusion of autogenous portosystemic shunts using methods commonly employed in transjugular intrahepatic portosystemic shunt (TIPS) reduction in four pediatric patients. Before treatment, the patients had hypoplastic, atrophic, or thrombosed portal veins. Following intervention, symptoms of overshunting resolved or improved in all patients without major complications. The innate plasticity of the pediatric portal venous system allowed for hypertrophy or development and maturation of cavernous transformations to accommodate increased hepatopetal blood flow and pressure.

HCV infection is associated with lower survival in simultaneous liver kidney transplant recipients in the United States.

The frequency of simultaneous liver kidney transplantation (SLKT) has been increasing over the past decade. Hepatitis C virus (HCV) infection is the most common indication for liver transplantation in the United States. Given the rising prevalence of HCV‐related SLKT, it is important to understand the impact of HCV in this patient population.

Underutilization of Living Donor Liver Transplantation in the United States: Bias against MELD 20 and Higher.

Abstract Background and Aims: Utilization of living donor liver transplantation (LDLT) and its relationship with recipient Model for End-Stage Liver Disease (MELD) needs further evaluation in the United States (U.S.). We evaluated the association between recipient MELD score at the time of surgery and survival following LDLT. Methods: All U.S. adult LDLT recipients with MELD < 25 were evaluated using the 1995–2012 United Network for Organ Sharing registry. Survival following LDLT was stratified into three MELD categories (MELD < 15 vs. MELD 15–19 vs. MELD 20–24) and evaluated using Kaplan-Meier methods and multivariate Cox proportional hazards models. Results: Overall, 2,258 patients underwent LDLT. Compared to patients with MELD < 15, overall 5-year survival following LDLT was similar among patients with MELD 15–19 (80.9% vs. 80.3%, p = 0.77) and MELD 20–24 (81.2% vs. 80.3%, p = 0.73). When compared to patients with MELD < 15, there was no significant difference in long-term post-LDLT survival among those with MELD 15–19 (HR: 1.11, 95% CI: 0.85−1.45, p = 0.45) and a non-significant trend towards lower survival in patients with MELD 20–24 (HR: 1.28, 95% CI: 0.91−1.81, p = 0.16). Only 14% of LDLTs were performed in patients with MELD 20–24 and the remaining 86% in patients with MELD < 20. Conclusion: LDLT is underutilized in patients with MELD 20 and higher.

Recurrent hepatocellular carcinoma and poorer overall survival in patients undergoing left-sided compared with right-sided partial hepatectomy.

Goals: We aimed to determine the incidence and predictors of recurrent hepatocellular carcinoma (HCC) after partial hepatectomy. Background: Liver transplantation is the preferred treatment for selected patients with HCC, but access to donor organs is limited. Partial hepatectomy is another accepted treatment option; however, postoperative recurrence is frequently observed. Methods: This is a retrospective cohort study of 107 consecutive patients who underwent partial hepatectomy for HCC between January 1993 and February 2011 at a US University Medical Center. Study endpoints were recurrent HCC, death, loss to follow-up, or last visit without HCC. Results: The study cohort was 78% male with a median age of 61 years and 59% Asians. A total of 50 patients developed recurrent HCC (46.7%) after a median follow-up of 12 (1 to 69) months postresection. Recurrent HCC was significantly higher in patients with left-sided resection (41% at year 1, 54% at year 2, 62% at year 3, 81% at year 4, and 90% at year 5) compared with right-sided resection (18% at year 1, 34% at year 2, 36% at year 3, 44% at year 4, and 72% at year 5). In multivariate Cox proportional hazards model also inclusive of anatomic resection and TNM stage 3/4, left-sided resection was significantly associated with increased HCC recurrence (hazard ratio, 2.13; P=0.02; 95% confidence interval, 1.08-4.2) compared with right-sided resection. Conclusions: HCC recurrence rate is higher among those undergoing left-sided resection: 54% at year 2 and 81% at year 4. Liver transplantation should be considered in patients who are at high risk for recurrence.

Fulminant Clostridium difficile Colitis in a Post-Liver Transplant Patient

A 36-year-old woman presented with a 2-day history of fever, malaise, abdominal distention and discomfort, and loose stools 3 months after liver transplantation for acetaminophen drug-induced liver injury with acute liver failure. The onset of her symptoms occurred shortly after completing a course of antibiotics, including nitrofurantoin and ciprofloxacin, for a urinary tract infection that she had developed 1 week before. In the emergency room, she was hypotensive and tachycardic and was resuscitated with intravenous fluids and was empirically started on broadspectrum antibiotics, including vancomycin, ertapenem, and metronidazole. Because her liver transplantation had been complicated by neurotoxicity due to the initial calcineurin inhibitor that was used and acute rejection, her current immunosuppressive regimen at presentation included cyclosporine and oral steroids; the former was discontinued and the latter converted into stress-dose systemic steroids. As her hypotension did not respond to fluid resuscitation, she was admitted to the intensive care unit, started on vasopressors and intubated given her impending respiratory failure from mechanical fatigue. Physical examination revealed an intubated and sedated slender woman, who was afebrile and normotensive, albeit on intravenous norepinephrine. She was anicteric, tachycardic without murmurs, and her lungs were clear. Her abdomen was very distended and firm, dull to percussion, with barely audible, hypoactive bowel sounds. Of note, her intraluminal bladder pressure was high, at 30 mmHg. She had no rash or edema. Although sedated, her pupillary reflexes were intact. Comprehensive laboratory studies were significant for leukocytosis with white blood cell (WBC) count 54.8 K/ll, hematocrit of 28%, bicarbonate level of 16 mmol/l, blood urea nitrogen level of 27 mg/dl, creatinine of 1.7 mg/dl, normal liver function tests except for a decreased albumin level of 1.1 g/dl, and INR of 1.7. Blood and urine cultures were negative but stool Clostridium difficile toxin B polymerase chain reactions (PCR) was positive. Serial abdominal X-rays revealed marked thumbprinting of the ascending and transverse colon, suggestive of severe colitis (Fig. 1). Given multiple organ failure and abdominal compartment syndrome from likely fulminant Clostridium difficile colitis, the patient underwent an emergent total abdominal colectomy with end ileostomy and Hartmann pouch. Intra-operatively, the transplanted liver and small bowel appeared normal, but the colon appeared pink and edematous throughout; 2 l of clear ascites were also found. Gross surgical pathology of the colon revealed the serosal surface to be pink and edematous, with scattered firm tanyellow focally aggregated plaques entirely in the serosal fat; however, the mucosa was diffusely pigmented black and covered a green-white purulent exudate (Fig. 2). Histology showed extensive severe acute pseudomembranous colitis with acute cryptitis, crypt abscesses, and mucosal ulceration, consistent with Clostridium difficile colitis (Fig. 3). M. Lee (&) T. J. Daugherty Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 300 Pasteur Dr., Always Bldg. M211, Stanford, CA 94305-5187, USA e-mail: maxlee@stanford.edu

Spontaneous liver rupture associated with hydatidiform mole pregnancy.

BACKGROUND: Spontaneous liver rupture is a rare occurrence during pregnancy. CASE: A young woman presented early in her pregnancy with severe abdominal pain, tachycardia, and hypotension. She was taken emergently to the operating room with a presumed diagnosis of ruptured ectopic pregnancy. Exploration revealed that her hemoperitoneum resulted from large fractures within her liver. During her resuscitation and treatment, a transvaginal ultrasound scan revealed a hydatidiform molar pregnancy. On resolution of postoperative complications and complete recovery, the patient was discharged home. CONCLUSION: This case illustrates that, although very unusual, hydatidiform molar pregnancies should be considered as a precipitating factor for spontaneous liver rupture.