Peter Crowley

Angiotensin-(1-7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat.

Ang-(1-7) (angiotensin-1-7), a peptide product of the recently described ACE (angiotensin-converting enzyme) homologue ACE2, opposes the harmful actions of AngII (angiotensin II) in cardiovascular tissues, but its role in liver disease is unknown. The aim of the present study was to assess plasma levels of Ang-(1-7) in human liver disease and determine its effects in experimental liver fibrosis. Angiotensin peptide levels were measured in cirrhotic and non-cirrhotic patients with hepatitis C. The effects of Ang-(1-7) on experimental fibrosis were determined using the rat BDL (bile-duct ligation) model. Liver histology, hydroxyproline quantification and expression of fibrosis-related genes were assessed. Expression of RAS (renin-angiotensin system) components and the effects of Ang-(1-7) were examined in rat HSCs (hepatic stellate cells). In human patients with cirrhosis, both plasma Ang-(1-7) and AngII concentrations were markedly elevated (P<0.001). Non-cirrhotic patients with hepatitis C had elevated Ang-(1-7) levels compared with controls (P<0.05), but AngII concentrations were not increased. In BDL rats, Ang-(1-7) improved fibrosis stage and collagen Picrosirius Red staining, and reduced hydroxyproline content, together with decreased gene expression of collagen 1A1, alpha-SMA (smooth muscle actin), VEGF (vascular endothelial growth factor), CTGF (connective tissue growth factor), ACE and mas [the Ang-(1-7) receptor]. Cultured HSCs expressed AT1Rs (AngII type 1 receptors) and mas receptors and, when treated with Ang-(1-7) or the mas receptor agonist AVE 0991, produced less alpha-SMA and hydroxyproline, an effect reversed by the mas receptor antagonist A779. In conclusion, Ang-(1-7) is up-regulated in human liver disease and has antifibrotic actions in a rat model of cirrhosis. The ACE2/Ang-(1-7)/mas receptor axis represents a potential target for antifibrotic therapy in humans.

Acute allograft rejection in human liver transplant recipients is associated with signaling through toll-like receptor 4.

Background and Aims:  Toll‐like receptor (TLR) signaling is a crucial step in initiating adaptive immune responses. In addition to recognizing endotoxin, TLR4 also recognizes endogenous ligands (‘damage‐associated structures’), which are released into the circulation in the peri‐transplantation period. TLR2 to a lesser extent also recognizes these endogenous ligands. Multiple studies involving solid organ transplants demonstrate a clear association between TLR4 and allograft rejection. In the present study we assessed whether an association exists between TLR4 and TLR2‐dependent responses and acute liver allograft rejection.

Post-Liver Transplantation Multicentric Castleman Disease Treated with Valganciclovir and Weaning of Immunosuppression

Multicentric Castleman disease is a lymphoproliferative disorder which when seen in the setting of HIV/AIDS is often associated with human herpes virus 8 (HHV‐8) infection. We describe the case of a HIV‐negative man who developed HHV‐8‐associated multicentric Castleman disease 11 years after liver transplantation. The patient presented with fevers and weight loss. Physical examination revealed enlarged cervical, axillary and inguinal lymph nodes. Widespread lymphadenopathy was confirmed on computed tomography (CT) scanning. Histology of an enlarged lymph node showed a polymorphous infiltrate with mature plasma cells, plasmacytoid lymphocytes and occasional blasts within the cortex and paracortex. The diagnosis of Castleman disease was confirmed by the finding of numerous HHV‐8‐immunopositive cells around the regressed lymph node follicles and the detection of HHV‐8 on plasma PCR. Although the conventional treatment for this condition has been combination chemotherapy, in the post‐transplant context it was decided to treat the patient with valganciclovir and cessation of immunosuppression. His symptoms resolved rapidly and repeat plasma PCR done 3 months after starting treatment was negative for HHV‐8. A follow‐up CT scan showed a dramatic reduction in the size and amount of lymphadenopathy. After 15 months of treatment, he remains well with no evidence of graft dysfunction or rejection.

Flucloxacillin-induced aplastic anaemia and liver failure.

Flucloxacillin is a commonly prescribed semisynthetic penicillinase‐resistant penicillin primarily used for the treatment of cutaneous staphylococcal infections. It is well‐recognized that flucloxacillin may occasionally result in fatal hepatic injury. We report the case of a 40‐year‐old woman who developed fulminant hepatic failure and aplastic anaemia following a course of oral flucloxacillin. At the time of transplantation the patient was severely neutropenic. Post‐transplant, the patient received single donor leucocyte transfusions, which resulted in a dramatic increase in neutrophil count. The patient was discharged from hospital after 120 days with normal liver function and recovered bone marrow. In this report, we discuss the care of patients with aplastic anaemia in the peritransplant setting.

Hodgkin lymphoma and fulminant hepatic failure

Hodgkin lymphoma (HL) most commonly presents as painless lymphadenopathy [1]. Much less commonly, liver abnormalities can be the initial manifestation. In one series of 421 consecutive patients with the disease, only six (1.4%) had liver abnormalities and no palpable lymphadenopathy, with the diagnosis made on liver biopsy [2]. In three (0.7%), at subsequent disease staging, lymphoma appeared to involve the liver solely, and only one developed hepatic failure. In another series, hepatic Hodgkin lymphoma accounted for only 0.07% of patients admitted to a Liver Failure Unit [3]. Fulminant hepatic failure (FHF) is a rare but important manifestation of HL. We report two cases of HL presenting with liver dysfunction that progressed rapidly to FHF, and in one case, necessitated urgent liver transplantation. A 19-year-old man presented in April 2007 with 4 weeks of fatigue and lethargy. He also had 2 weeks of progressive jaundice and anorexia. There was no fever, night sweats, or a viral prodromal illness. He was not on any regular medication but had had an alcohol binge the weekend before falling ill. Initial physical examination was unremarkable apart from jaundice and an abdominal maculopapular rash. There was no hepatosplenomegaly or palpable lymphadenopathy. In 2001, he was diagnosed with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) stage I. He achieved complete remission after five cycles of ABV (doxorubin, bleomycin, and vinblastine) chemotherapy with prednisolone, but relapsed in March 2005 with cervical adenopathy and received eight cycles of intensified BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone). Thereafter, he achieved remission and was well until April 2007. At this presentation, initial laboratory tests revealed liver dysfunction, with total bilirubin 591 mmol/L, alkaline phosphatase (ALP) 197 U/L (reference range [RR] 32–91), alanine transaminase (ALT) 3866 U/L (RR:545), and g-glutamyl transferase (GGT) 103 U/L (RR:555). International normalized ratio (INR) was 2.5, albumin 30 g/L, and lactate dehydrogenase (LDH) 540 U/L (RR: 100–200). Serological tests for viral hepatitis A, B, and C and human immunodeficiency virus (HIV) were negative, as were autoimmune studies. Paracetamol was undetected in blood, and copper studies were normal. Imaging revealed hepatomegaly (15.1 cm) without focal lesions and splenomegaly (14.7 cm) but no lymphadenopathy. A liver biopsy showed non-specific severe acute hepatitis with extensive multiacinar necrosis. No lymphoma cells were identified. There was no significant hepatocellular iron deposition. Immunohistochemical stains for Epstein–Barr virus (EBV) and cytomegalovirus were negative. Biopsy of the abdominal rash raised the possibility of erythema multiforme. Hepatic failure rapidly progressed over the following week with encephalopathy and worsening coagulopathy, leading to urgent liver transplant despite no clear diagnosis. The postoperative course was uneventful.

An autosomal dominant form of non-cirrhotic portal hypertension

To the Editor: The familial aggregation idiopathic non-cirrhotic portal hypertension (INCPH) has been previously described, however, there have been no reports of Mendelian inheritance [1–5]. We describe the first case of autosomal dominant inheritance of INCPH in a single family. Fig. 1 demonstrates the autosomal dominant inheritance pattern, including male-to-male transmission. I.6 suffered a fatal variceal haemorrhage and may have also been affected. In this patient however, secondary causes of portal hypertension could not be excluded given the lack of a comprehensive medical record. INCPH was diagnosed in all cases in accordance with criteria proposed by Schouten [6], excluding II.1 who died prior to liver biopsy being performed. The siblings and children of affected family members have been screened with upper gastrointestinal endoscopies, hepatosplenic ultrasound and full blood examination.

Identifying the superior measure of rapid fibrosis for predicting premature cirrhosis after liver transplantation for hepatitis C

Hepatitis C virus (HCV) recurrence post liver transplant is universal, with a subgroup of patients developing rapid hepatic fibrosis. Various clinical definitions of rapid fibrosis (RF) have been used to identify risks for rapid progression, but their comparability and efficacy at predicting adverse outcomes has not been determined.

Education and imaging. Gastrointestinal: refractory ulcerative colitis complicated by colonic stricturing endometriosis.

A 25 year-old woman with a 15 year history of refractory ulcerative colitis on maintenance azathioprine, and mesalazine, presented with several months of increasing colicky abdominal pain and distension, bloody diarrhea and malaise. Symptoms failed to respond to repeated courses of steroids and were worse around her period. On physical exam, her abdomen was mildly distended with tenderness to deep palpation in the left lower quadrant with normal bowel sounds. Colonoscopy revealed florid changes of ulcerative colitis in the rectum with mucosal hemorrhage and colonic stricturing at the recto-sigmoid junction preventing full colonoscopy (Figure 1). Histology of biopsy specimens taken from the area of stricture showed areas of ulceration with underlying inflamed granulation tissue consistent with ulcerative colitis. There were no granulomata, dysplasia or malignancy. Laboratory analysis revealed mild neutrophilia and mild elevation of inflammatory markers. As her abdominal pain, distension and bleeding became increasingly severe, she was referred to a colorectal surgeon who performed laparoscopy which revealed extensive pelvic endometriosis that had obliterated the Pouch of Douglas and fused the rectum to the back of the uterus. A laparoscopic-assisted proctocolectomy and W pouch with ileostomy and radical excision of pelvic endometriosis including Pouch of Douglas was performed. Histology of the resection specimen showed severe chronic ulcerative proctocolitis involving the rectum and sigmoid colon with moderate stricture formation with proximal colon dilatation, negative for malignancy. Extensive endometriosis was seen infiltrating the rectal wall (Figure 2) as well as the subserosal muscularis of the appendix. This case illustrates that intestinal endometriosis can mimic and co-exist with other intestina diseases, producing similar clinical symptoms and similar pathological changes. Intestinal endometriosis has previously been reported to cause proctitis with mucosal ulceration, rectal masses, colonic obstruction and strictures. In this case, this young woman had dual pathology and her endometriosis diagnosis was masked by the long standing diagnosis of ulcerative colitis. Indeed it was not suspected as both conditions can produce exacerbations around menstruation. Intestinal endometriosis is potentially missed with endoscopic biopsies as they usually involved the serosa and muscularis propria, sparing the mucosa and the majority of cases are diagnosed only after colectomy. Surgical intervention in this particular case has benefited in management of symptoms in both conditions. It is therefore important to consider a differential diagnosis of intestinal endometriosis, especially in a young female who has distal, refractory inflammatory bowel disease.

Intravascular large B cell lymphoma: an elusive cause of pyrexia of unknown origin diagnosed postmortem.

Intravascular large B cell lymphoma (IVLBCL) is a rare cause of pyrexia of unknown origin. Because of its protean clinical manifestations, diagnosis is elusive and is often made postmortem. We report here a case of IVLBCL that evaded diagnosis despite multiple investigations in vivo for pyrexia of unknown origin over a 5‐month period.

Systemic mastocytosis: a gastroenterological perspective

A 53 year old woman presented with abnormal liver function tests and subsequently developed intermittent abdominal pain, vomiting and diarrhoea. There were no rash or anaphylactoid reactions. Endoscopic biopsies showed excessive density of eosinophils and immunohistochemical staining for tryptase revealed a florid mast cell infiltrate. A diagnosis of systemic mastocytosis was made by bone marrow biopsy. Systemic mastocytosis is a rare myeloid neoplasm often associated with gastrointestinal symptoms due usually to mediator release but may rarely represent organ infiltration. While endoscopic and routine biopsy appearances are non-specific, suggestive features should lead to staining for mast cell tryptase or CD 117. However, diagnose generally requires bone marrow biopsy. The prognosis in the majority of patients is good and supportive management only is required. For patients with aggressive disease, cytoreductive therapy may be needed.