Liver involvement in celiac disease

Celiac disease may present as a cryptogenic liver disorder being found in 5–10% of patients with a persistent and cryptogenetic elevation of serum aminotransferase activity. In fact, a wide spectrum of liver injuries in children and adults may be related to CD and in particular: (1) a mild parenchymal damage characterised by absence of any clinical sign or symptom suggesting a chronic liver disease and by non-specific histological changes reversible on a gluten-free diet; (2) a chronic inflammatory liver injury of autoimmune mechanism, including autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis, that may lead to fibrosis and cirrhosis, generally unaffected by gluten withdrawal and necessitating an immunosuppressive treatment; (3) a severe liver failure potentially treatable by a gluten-free diet. Such different types of liver injuries may represent a spectrum of a same disorder where individual factors, such as genetic predisposition, precocity and duration of exposure to gluten may influence the reversibility of liver damage. A rigorous cross-checking for a asymptomatic liver damage in CD individuals and conversely, for CD in any cryptogenic liver disorder including end-stage liver failure is recommended.     

Romiplostim treatment allows for platelet transfusion‐free liver transplantation in pediatric thrombocytopenic patient with primary sclerosing cholangitis

Thrombocytopenia is a major risk factor for cirrhotic liver disease. Patients with thrombocytopenia may have esophageal or gastric varices secondary to portal hypertension, leading to variceal bleeding which exposes the liver to further damage. Here, we present a female pediatric patient with PSC and CD, whose progressive thrombocytopenia was successfully controlled by romiplostim, a TPO receptor agonist. The patient developed bloody diarrhea at four yr of age, and was subsequently diagnosed with PSC and CD when seven yr old. While CD was well‐controlled by immunomodulators, the patient's thrombocytopenia gradually progressed resulting in petechiae (platelet count of 11 × 10⁹/L) when she was 10 yr and four months old. She responded poorly to immunoglobulin and corticosteroids. Weekly subcutaneous injection of romiplostim was therefore initiated, and platelet counts were maintained over at 50 × 10⁹/L. She was able to undergo successful LDLT without platelet transfusion seven months after the initiation of romiplostim. Romiplostim was not required after LDLT with improved platelet counts. This case report suggests that romiplostim may be effective in the treatment of thrombocytopenic children with liver cirrhosis and portal hypertension, and in eliminating the need for platelet transfusion during the peri‐transplant period.     

Heterozygote to homozygote related living donor liver transplantation in maple syrup urine disease: A case report

Liver transplantation is an accepted treatment modality in the management of MSUD. To our knowledge, ours is only the second successful case to date of a patient with MSUD receiving an allograft from an RLD who is a heterozygous carrier for the disease. In view of the worldwide shortage of available organs for transplantation, heterozygote to homozygote transplantation in the setting of MSUD may provide a viable alternative for those awaiting transplantation. We report on the case of a two‐yr‐old infant with MSUD, who received a left lateral segment (segments II and III) liver transplant from his mother, a heterozygote carrier of one of the three abnormal genes implicated in MSUD. Post‐operative BCAA levels normalized in our patient and remained so on an unrestricted protein diet and during times of physiological stress. To date, this is only the second case of a successful RLD liver transplant in a child with MSUD. Preliminary results indicate that RLD liver transplants are at least equivalent to deceased donor liver transplants in the treatment of MSUD, although longer term follow‐up is required. Heterozygote to homozygote RLD transplant in patients with MSUD presents a new pool of potential liver donors.     

Liver transplantation in a child with liver failure due to chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from the same unrelated living donor

Englert C, Ganschow R. Liver transplantation in a child with liver failure due to chronic graft‐versus‐host disease after allogeneic hematopoietic stem cell transplantation from the same unrelated living donor. Abstract: We report a case of a six‐yr‐old boy who developed chronic GVHD of the liver, intestines, and skin following allogeneic hematopoietic SCT. The boy received an allogeneic hematopoietic stem cell transplant at the age of two yr because of early recurrence of ALL. Chimerism analysis showed complete chimerism. In the following year, he developed GVHD despite adequate immunosuppressive therapy. Liver biopsy showed liver GVHD resulting in liver cirrhosis by the age of five yr. LTx was performed with a left liver lobe from the unrelated donor from whom the stem cells had been taken. Immunosuppressive therapy consisted of low‐dose steroids and low‐dose cyclosporine. The postoperative course was uneventful. Graft function was excellent, and we performed protocol biopsies at seven days and three wk as well as three, six, and nine months after transplantation; none of these showed any signs of rejection or GVHD. Immunosuppressive therapy was discontinued nine months after LTx. Three yr after transplantation, the boy is in good condition with normal graft function. To our knowledge, this is the first report on LTx following allogeneic hematopoietic SCT from the same unrelated living donor.     

Cryptosporidial infections after solid organ transplantation in children

The diagnosis and treatment of moderate-to-severe diarrhea in solid organ transplant recipients is often a challenge because of the variety of infectious and non-infectious causes. The morbidity associated with this clinical condition is of particular significance in the pediatric population where malnutrition may lead to poor growth and development. Rarely, Cryptosporidium has been identified as the cause of clinically significant diarrhea in pediatric solid organ transplant patients. A retrospective review identified cases of cryptosporidiosis among the 1160 non-renal, abdominal organ transplant recipients cared for at the Children's Hospital of Pittsburgh between 1981 and June 1998. Four cases of clinically significant diarrhea were identified in three liver transplant recipients and one small bowel transplant recipient. Endoscopy and biopsy with histologic confirmation diagnosed three cases; ova and parasitic examination of stool specimens identified the fourth case. Therapy varied among the patients depending on when they had been diagnosed as, over the years, different and newer agents have been indicated for the treatment of cryptosporidiosis. All four patients resolved their infections. Hence, endoscopy and biopsy is recommended for pediatric transplant patients who present with chronic diarrhea of unknown etiology. The patients who may be at a higher risk for cryptosporidial infections include those with an increased immunosuppressive state (i.e. pre-existing immunodeficiency, malignancy, re-transplantation, and those receiving higher doses of immunosuppressive therapy). While cryptosporidiosis is a non-lethal complication, it allows the clinician to gain further insight into the degree of immunosuppression of their patient.     

Development of hepatopulmonary syndrome and portopulmonary hypertension in a paediatric liver transplant patient

BACKGROUND: Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH) are pulmonary vascular disorders which occur in patients with severe liver disease and/or portal hypertension. Although these syndromes are frequently diagnosed in patients undergoing assessment for liver transplantation, they seldom occur in the same patient. METHOD: This report describes a female paediatric patient, born with extra-hepatic biliary atresia, who required liver transplantation, at the age of 15, for secondary biliary cirrhosis. She had severe HPS prior to her first liver transplant, which resolved rapidly following surgery, as well as indirect evidence for PPH. She required a second liver transplant 1 yr later for chronic rejection. Whilst evaluating the patient for a third liver transplant, 4 yr later, severe PPH was discovered. The patient died 3 months later from right heart failure. CONCLUSION: HPS and PPH may coexist however they may show differing responses to liver transplantation with progression of PPH despite the resolution of HPS.     

Living donor liver transplantation in maple syrup urine disease – Case series and world's youngest domino liver donor and recipient

MSUD occurs due to deficiency of enzyme BCKAD required for metabolism of leucine, isoleucine, and valine leading to the accumulation of these and their ketoacids causing acute metabolic decompensation manifesting as encephalopathy or sudden death. The patient requires special protein‐restricted diet to survive. As this enzyme is expressed in liver, liver transplantation has been successfully performed as a cure. We report two patients of MSUD who underwent LDLT while their livers were used as a domino graft for other biliary cirrhotic patients. A 22‐month‐old male child diagnosed as a case of classic MSUD underwent LDLT from an altruistic aunt as donor following which his serum leucine levels normalized on an unrestricted protein diet. His liver was used as a domino graft. A 38‐month‐old female child with diagnosed MSUD underwent LDLT from a swap donor, and her liver was used as a domino graft. Her DQ improved post‐transplant. LDLT from non‐heterozygous donors is a cure for classical MSUD. Their livers can be used as domino grafts for non‐MSUD cases.     

Living related liver transplant following bone marrow transplantation from same donor: Long‐term survival without immunosuppression

Granot E, Loewenthal R, Jakobovich E, Gazit E, Sokal E, Reding R. Living related liver transplant following bone marrow transplantation from same donor: Long‐term survival without immunosuppression.
Pediatr Transplantation 2012: 16: E1–E4. © 2010 John Wiley & Sons A/S. Abstract: We report long‐term (seven yr) immunological tolerance in a 16‐yr‐old boy, to a liver allograft donated by his father following a bone marrow transplant at age 2.5 yr from the same donor. The bone marrow transplant was complicated by severe GVHD leading to liver failure and the ensuing need for a liver transplant, performed under planned avoidance of immunosuppression. At one wk post‐transplant, although a liver biopsy was histologically compatible with acute rejection, favorable clinical and biochemical evolution precluded initiating immunosuppressive therapy, thus highlighting the need for caution when interpreting early histological changes so that administration of unnecessary immunosuppression can be avoided. Induction of tolerance in transplant recipients remains an elusive goal. In those patients who had received conventional bone marrow transplants and had endured the consequences of GVHD, development of macrochimerism may allow immunosuppression‐free solid organ transplantation from the same donor.     

Bone marrow engraftment and associated dermatologic sequelae in a three‐yr‐old after liver transplantation

We present a case of a three‐yr‐old child with a history of multisystem Langerhans cell histiocytosis treated with systemic chemotherapy, who developed progressive liver failure and received an orthotopic split liver transplant while continuing on chemotherapy. One month following transplant, he developed acute graft‐vs.‐host disease of the skin and gastrointestinal tract. Peripheral blood chimerism studies post‐transplant demonstrated an increasing predominance of donor lymphocytes and granulocytes. Shortly after, the patient developed vitiligo, and two yr after transplantation, the patient developed skin manifestations of psoriasis. We discuss and review the current literature, which demonstrates that chimerism following liver transplantation is rare and in our patient may be related to his profound immunosuppression around the time of liver transplant as well the development of acute graft‐versus‐host disease. While autoimmune disease can occur after solid organ and stem cell transplant, our patient developed skin manifestations of autoimmunity after liver transplantation, which is also rarely described.     

Novel protocol including liver biopsy to identify and treat CD8+ T‐cell predominant acute hepatitis and liver failure

In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune‐mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T‐cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue‐based approach to diagnosis and treatment that may improve transplant‐free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy.     

Obesity in adolescents with celiac disease: two adolescents and two different presentations

Celiac disease (CD) usually presents with diarrhea and growth retardation in childhood. Obesity is one of the paradoxical conditions in children with CD. We present two adolescents with CD and obesity. One of these patients was diagnosed as CD with malnutrition. His body weight had returned to normal after a gluten-free diet, and after stopping the diet, he had become obese. The second patient was an obese adolescent presenting with dyspeptic symptoms who was diagnosed as CD. Although rare, pediatricians should remember that obesity might be seen in CD before or after the diagnosis.     

Extrahepatic portal vein aneurysm after liver transplantation in a child: Case report

Molinares B, Álvarez S, García V, Sepúlveda ME, Yepes NL, Peláez S. Extrahepatic portal vein aneurysm after liver transplantation in a child: Case report. Abstract: Portal vein aneurysms are very rare and represent <3% of all venous aneurysms. They can be congenital or acquired. Most patients do not have liver disease at diagnosis. Although uncommon, portal vein aneurysm has been described after liver transplant. We report the case of a six‐yr‐old girl who presented with an aneurysm of the extrahepatic portal vein after segmental liver transplantation. Because the patient was asymptomatic and owing to its extrahepatic location, this aneurysm has been successfully followed by clinical exam and imaging for four yr.     

Incidentally detected cholangiocarcinoma in an explanted liver with biliary atresia after Kasai operation

This report presents the case of a 30‐yr‐old woman with BA who developed incidental cholangiocarcinoma following the Kasai operation. She showed progressive liver dysfunction and cirrhosis at the age of 30 yr and underwent LDLT. A 4‐cm‐diameter liver tumor in the anastomotic site of portoenterostomy was incidentally found as a result of a pathological examination of the explanted native liver. The tumor was pathologically diagnosed to be intrahepatic cholangiocarcinoma. Although cholangiocarcinoma in patients with BA has been previously reported in only three cases, it should be nevertheless always considered in the differential diagnosis of hepatic tumors during a long follow‐up course in patients with BA.     

Long-term study of patients with coeliac disease in childhood and adolescence: latent and transient coeliac disease

Coeliac disease (CD) is known as a lifelong condition of gluten intolerance. In case of some patients, the time after which gluten exposition leads to damage of the small intestinal mucosa may be very long. In addition to the florid form of CD, there are also silent (atypical mono- and oligosymptomatic with typical damage of the small intestinal mucosa) and latent forms (often asymptomatic without clear mucosal changes, antibody titres often normal). Occasionally the development of gluten tolerance is postulated (transient CD). We investigated 47 subjects diagnosed in childhood definitely as CD patients. In the age of 16.3 +/- 4.8 years, the patients started a gluten containing diet. After 6 to 9 months of gluten containing diet a small intestinal biopsy was performed in all patients. Surprisingly we found 11 patients with normal small intestinal mucosa (group 1). The other 36 patients showed a flattened mucosa as expected (group 2). The further development of group 1 was followed. In 9 patients a further biopsy was performed after more than 2 (at maximum after 8.1) years of gluten containing diet. In all patients the morphology of the mucosa was normal. In 7 of 11 cases normal numbers of intraepithelial lymphocytes were counted. Only in two patients raised titres of gliadin and endomysium antibodies were found after 4.5 and 15 years of gluten containing diet. In the other 9 patients no increase in antibody titers was found up to 10.3 years. However, in group 1, mucosal lactase activity was decreased as was also the case for group 2. Conclusion: A high number of adolescent coeliac patients does not respond or responds only minimally to reintroduction of gluten into the diet over a period longer than two years. These patients should regularly be further controlled serologically.     

The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman's disease

We present the unique case of a pediatric patient who received chemotherapy for a diagnosis of CD, while mechanically supported with a Berlin EXCOR LVAD secondary to restrictive cardiomyopathy. A four‐yr‐old previously healthy male with restrictive cardiomyopathy required MCS after cardiac arrest but was diagnosed with multicentric CD, a non‐malignant lymphoproliferative disorder fueled by excessive IL‐6 production. Treatment with IL‐6 blockade (tocilizumab) every two wk and methylprednisolone had no effect on his lymph nodes or cardiac function while on temporary RotaFlow. A Berlin LVAD was placed for treatment with rituximab, COP, vincristine, and methylprednisolone. After three courses of chemotherapy, his inflammatory markers normalized and his lymphadenopathy decreased but cardiac function remained severely depressed. He tolerated chemotherapy on the Berlin but required frequent titrations of his anti‐coagulation regimen and he did suffer a hemorrhagic stroke. His clinical status improved significantly with rehabilitation, and he tolerated heart transplantation without further complications. MCS is a feasible option as a bridge to recovery or heart transplant eligibility for patients with hemodynamic collapse requiring chemotherapy but it does necessitate close titration of the anti‐coagulation regimen to coincide with changes in the inflammatory state.     

Transmission of clear cell tumor in a graft liver from cadaveric donor: Case report

Backes AN, Tannuri ACA, de Mello ES, Gibelli NEM, de Castro Andrade W, Tannuri U. Transmission of clear cell tumor in a graft liver from cadaveric donor: Case report. Abstract: Neoplasms in children after organ transplantation are related to the type and intensity of immunosuppression and the donor–recipient serostatus, especially in relation to the Epstein–Barr virus. The patient was a two‐yr‐old female child with biliary atresia who underwent a liver transplantation from a female cadaver donor. Two adults received kidney transplants from the same donor. Nine months after transplantation, one of the adult recipients developed an urothelial tumor in the kidney graft. Imaging tests were repeated monthly in the liver‐transplanted child and revealed no abnormalities. However, one yr and two months after the transplantation, the patient developed episodes of fever. At that time, imaging and liver biopsy showed a clear cell tumor of urothelial origin in the graft and the disease was limited to the liver. The patient underwent liver retransplantation, and she is currently free of tumor recurrence. Although rare, the occurrence of tumors in the post‐transplant period from cadaver donors, without previously diagnosed tumors, is one of the many problems encountered in the complex world of organ transplantation.     

De novo inflammatory bowel disease after pediatric kidney or liver transplant

A subset of children who receive a liver and/or kidney transplant develop de novo inflammatory bowel disease‐like chronic intestinal inflammation, not explained by infection or medications, following transplant. We have conducted a single‐center, retrospective case series describing the unique clinical and histologic features of this IBD‐like chronic intestinal inflammation following solid organ transplant. At our center, nine of 327 kidney or liver recipients developed de novo IBD following transplant (six liver, two kidney, one liver‐kidney). Most children presented with prolonged hematochezia and diarrhea and were treated with aminosalicylates. At time of diagnosis, five were not currently using mycophenolate mofetil for transplant immunosuppression. Histologic and endoscopic findings at IBD diagnosis included inflammation, ulcerations, granulomas, and chronic colitis. Since diagnosis, no patients have required surgical intervention, or escalation to biologic therapy, nor developed stricturing or perianal disease. In this case series, de novo post‐transplant IBD developed in 4% of pediatric liver and/or kidney recipients; however, it often does not fit the classic patterns of Crohn's disease or ulcerative colitis.     

Successful treatment of de novo autoimmune hepatitis and cirrhosis after pediatric liver transplantation

Over a 15-yr period of observation, among the 205 children who underwent liver transplantations, one of them developed a particular type of late graft dysfunction with clinical and histological similarity to autoimmune hepatitis. The patient had alpha1-antitrypsin deficiency and did not previously have autoimmune hepatitis or any other autoimmune disease before transplantation. Infectious and surgical complications were excluded. After repeated episodes of unexplained fluctuations of liver function tests and liver biopsies demonstrating reactive or a biliary pattern, without any corresponding alteration of percutaneous cholangiography, a liver-biopsy sample taken 4 yr after the transplant showed active chronic hepatitis progressing to cirrhosis, portal lymphocyte aggregates, and a large number of plasma cells. At that time, autoantibodies (gastric parietal cell antibody, liver-kidney microsomal antibody, and anti-hepatic cytosol) were positive and serum IgG levels were high. Based on these findings of autoimmune disease, a diagnosis of 'de novo autoimmune hepatitis' was made. The treatment consisted of reducing the dose of cyclosporine, reintroduction of corticosteroids, and addition of mycophenolate mofetil. After 19 months of treatment, a new liver-biopsy sample showed marked reduction of portal and lobular inflammatory infiltrate, with regression of fibrosis and of the architectural disruption. At that time, serum autoantibodies became negative. The last liver-biopsy sample showed inactive cirrhosis and disappearance of interface hepatitis and of plasma cell infiltrate. Presently, 9 yr after the transplantation, the patient is doing well, with normal liver function tests and no evidence of cirrhosis. Her immunosuppressive therapy consists of tacrolimus, mycophenolate mofetil, and prednisolone. In conclusion, the present case demonstrates that de novo autoimmune hepatitis can appear in liver-transplant patients despite appropriate anti-rejection immunosuppression, and triple therapy with tacrolimus, mycophenolate mofetil, and prednisolone could sustain the graft and prevent retransplantation.     

New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney–liver complications

Improved neonatal medical care and renal replacement technology have improved the long‐term survival of patients with ARPKD. Ten‐yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra‐ and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto‐systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat‐soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato‐biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age‐matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64–80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato‐biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to <10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver–kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver–kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.     

Is single‐port laparoscopy feasible after liver transplant?

The role of laparoscopy following liver transplant in children is debated. Herein, we report the first two cases of SIPES post‐liver transplant. In both patients, SIPES access was carried out using Olympus TriPort. Patient 1 was an 11 yr old born with biliary atresia, who had four previous major laparotomies: Kasai portoenterostomy, followed by liver transplant and two laparotomies for lymph node biopsies for PTLD. The child was referred for suspected PTLD relapse due to enlarged nodes on CT scan. At SIPES, following adequate adhesiolysis, the lymph node biopsy was achieved successfully. Patient 2 was a five yr old with bilateral intra‐abdominal testes who had undergone liver transplant aged two yr. He underwent a left one‐stage orchidopexy and right first‐stage Fowler–Stephen procedure at five yr of life, followed by a second stage Fowler–Stephen surgery on the right side, nine months later. All procedures were successfully performed by SIPES, and both patients were discharged home on first post‐operative day. We conclude that SIPES could be safely carried out in patients who have had liver transplant. In case of diffuse intraperitoneal adhesions, SIPES is beneficial to create space by blunt and sharp dissection and decreases post‐operative stay.