Neutrophilic Cholangitis Research Articles

Gastrointestinal and hepatic manifestations in patients with generalised pustular psoriasis.

Generalised pustular psoriasis (GPP) is a rare and severe form of pustular psoriasis. It is defined by persisting or relapsing macroscopically visible sterile primary pustules occurring on non-acral skin and not within psoriasis plaques. Due to its rarity, there is a lack of randomised controlled trials on GPP and its associated gastrointestinal (GI) and liver disorders. In this article, we present a review of the GI and hepatic disorders associated with GPP. GPP is known to be associated with extracutaneous manifestations such as neutrophilic cholangitis. Abnormal liver function tests are reported in up to 90% of patients with GPP upon diagnosis. Less commonly, pancreatitis and gastrointestinal bleeding have been attributed to GPP. While a psoriasis registry with 7.5% prevalence of pustular psoriasis reported an association with viral hepatitis B and C, the true relationship remains to be elucidated as hepatitis B is endemic in Asia where GPP prevalence is higher. Common genetic mutations between GPP and conditions such as hepatocellular carcinoma and inflammatory bowel disease have been identified, explaining their possible associations and providing answers to potential therapeutic options for these conditions. A lack of recognition of these association may result in unnecessary withdrawal of efficacious and definitive drugs for the treatment of GPP. Understanding the characteristics of the associated GI and hepatic disorders will have important implications for targeting the appropriate therapeutics.

Clinical Course and Characteristics of Generalized Pustular Psoriasis

Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterized by episodes of widespread sterile macroscopic pustules, with or without systemic inflammation and/or plaque psoriasis. Multiple GPP subtypes have been described, from acute GPP of von Zumbusch to milder, annular pustular psoriasis. Generalized pustular psoriasis mainly affects adults, with a female preponderance, but juvenile GPP also occurs. Flares are a hallmark of GPP and may occur de novo or be provoked by triggers, including withdrawal of systemic corticosteroids, infections, stress, pregnancy, and menstruation. Severity of flares varies widely between patients, and between flares in an individual patient. Significant flares are often accompanied by systemic symptoms, notably fever, general malaise, and extracutaneous manifestations such as arthritis, uveitis, and neutrophilic cholangitis. Common laboratory abnormalities include neutrophilia, elevated C-reactive protein levels, hypocalcemia, and abnormal liver function tests. The clinical course of GPP is highly variable; it can be a relapsing disease with recurrent flares and no pustulation between flares or a persistent disease with perpetual mild pustulation punctuated with flares of greater severity. Patients may have multiple flares per year or a flare every few years. Most flares last 2–5 weeks and approximately 50% require hospitalization. Life-threatening complications include sepsis and renal, hepatic, respiratory, and heart failure. Reported mortality rates are 2–16%.

Secondary sclerosing cholangitis: a lesser known side effect of pembrolizumab therapy

Abstract Introduction/Objective Immune check-point inhibitors have increasingly taken hold as mainstays of various cancer treatments, revolutionizing outcomes for individuals diagnosed with terminal malignancy. Hepatotoxicity is reported to occur in 2-10% patients, predominantly manifesting as a mixed cholestatic hepatitis pattern of injury. Cholangitis is a rare immune-mediated adverse event (irAE). We present a case of pembrolizumab-induced secondary sclerosing cholangitis presenting with multiple biliary strictures. Early recognition is crucial as these cases are resistant to treatment with steroids. Methods/Case Report 82-year-old woman with recurrent, metastatic, high grade urothelial carcinoma status post cystectomy and neoadjuvant chemotherapy, presented with new onset obstructive jaundice (alkaline phosphatase 958 U/L, aspartate aminotransferase of 331 U/L, alanine aminotransferase of 422 U/L, and total bilirubin of 19.8 mg/dL) following two weeks of pembrolizumab therapy. MRCP suggested intrahepatic biliary ductal dilation. ERCP showed multiple strictures involving hepatic bifurcation, left, right and intrahepatic ducts with beaded intrahepatic bile ducts. Liver biopsy showed expanded portal tracts with mixed inflammatory infiltrate, extensive bile duct injury, neutrophilic cholangitis, ductular proliferation, and perivenular cholestasis (10% dropout) concerning for mechanical obstruction. CK7 did not show ductopenia and immunostain IgG4 was negative. All autoimmune work-up was negative. Liver enzymes continued to rise despite multiple therapeutic stents, drains, high-dose corticosteroids, ursodiol and mycophenolate mofetil. The patient died five months later. Results (if a Case Study enter NA) NA Conclusion Pemrolizumab-induced secondary sclerosing cholangitis is a rare, hence under-recognized, adverse effect of check point inhibitor-mediated hepatotoxicity. It is important to recognize this association, as it has limited benefit from steroid therapy. Our finding of pembrolizumab-related SC adds to the growing body of literature of immune check-point inhibitor-related hepatobiliary injury and calls for further characterization of PD-1/PD-L1 inhibitor SC and its clinical implications.

Histological Patterns of Hepatitis and Cholangitis

Histological Patterns of Hepatitis and Cholangitis

Serum Matrix Metalloproteinase 7 Is a Diagnostic Biomarker of Biliary Injury and Fibrosis in Pediatric Autoimmune Liver Disease.

In autoimmune liver disease (AILD), including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and overlap syndrome of AIH and PSC (ASC), the presence of biliary injury portends a worse prognosis. We studied serum matrix metalloproteinase 7 (sMMP7) as a biomarker for pediatric sclerosing cholangitis (SC). We prospectively enrolled 54 children (median age, 16 years) with AILD (AIH, n = 26; ASC, n = 16; and PSC, n = 12) at our center. The sMMP7 concentrations were higher in patients with SC compared to those without cholangiopathy (P < 0.001). An sMMP7 concentration >23.7 ng/mL had a sensitivity and specificity of 79% and 96%, respectively, and outperformed alkaline phosphatase (ALP) and gamma‐glutamyltransferase (GGT) in segregating patients with SC. Serum concentrations correlated with liver gene expression levels for MMP7 (r = 0.70; P < 0.001). Using immunofluorescence, MMP7 was localized primarily to the cholangiocytes of patients with SC. In 46 subjects with liver biopsy available for blinded review, elevation in sMMP7 concentrations segregated with the presence of lymphocytic and neutrophilic cholangitis and periductal fibrosis and correlated with Ishak, Ludwig, and Nakanuma scoring systems. Liver stiffness measured by magnetic resonance elastography also correlated with sMMP7 concentrations (r = 0.56; P < 0.01). Using magnetic resonance cholangiopancreatography plus (MRCP+), sMMP7 in 34 patients correlated with the number of biliary dilatations (r = 0.54; P < 0.01) and strictures (r = 0.56; P < 0.01). MMP7 as a marker of biliary injury was validated in an independent cohort of children with ulcerative colitis. Higher sMMP7 concentrations also correlated with a history of SC‐related complication. Conclusion: MMP7 is a promising biomarker for pediatric SC that diagnostically outperforms ALP and GGT. sMMP7 may directly reflect biliary injury and fibrosis, the main drivers of disease progression in SC.

Retrospective study of the relative frequency of feline hepatobiliary disease in New Zealand based on 10 years of hepatic biopsy samples

AimsTo retrospectively determine the relative frequency of feline hepatobiliary diseases from biopsy specimens submitted to a single laboratory across a 10-year period and to establish whether age, sex or breed...

Histopathological frequency of feline hepatobiliary disease in the UK.

To determine the histopathological frequency of feline hepatobiliary diseases in the UK and to identify breed, age and gender predispositions to developing individual diseases. Histopathology results from 1452 feline liver biopsies were assessed. A control population of microchipped cats was used for breed comparison. Data were retrospectively categorised into hepatobiliary diseases according to World Small Animal Veterinary Association standards. Odds ratios and 95% confidence intervals were calculated to determine breed predispositions to the 10 most frequent diseases. Gender and age distributions were also evaluated. The most frequent diseases based on histopathology were neutrophilic cholangitis (20·5%), reactive hepatitis (20·4%), reversible hepatocellular injury (8·4%), lymphocytic cholangitis (6·8%), biliary cysts (5·7%), acute hepatitis (5·6%), haematopoietic neoplasia (5·6%), hepatocellular neoplasia (4·9%), congenital portosystemic shunt (3·8%) and cholangiocellular neoplasia (3·1%). Some previously unreported breed and age predispositions were identified. This is the first study to document the histopathological frequency of hepatobiliary diseases in a large cohort of cats in the UK, as well as novel breed and age predispositions. These data may help increase the index of suspicion of a particular disease in the absence of a biopsy-confirmed diagnosis.

Cholangitis and Cholangiohepatitis in Dogs: A Descriptive Study of 54 Cases Based on Histopathologic Diagnosis (2004-2014).

BackgroundCholangitis in dogs appears to be more common than previously thought, but understanding of the disease remains incomplete.ObjectiveTo describe a population of dogs with cholangitis or cholangiohepatitis.AnimalsFifty‐four client‐owned dogs with cholangitis or cholangiohepatitis.MethodsMedical records of dogs with cholangitis or cholangiohepatitis confirmed by histopathology between January 2004 and December 2014 were identified using a computer‐based search and retrospectively reviewed.ResultsClinical signs included vomiting (72.2%), lethargy (70.4%), and inappetence (64.8%). Most dogs (49/50) had increased liver enzyme activities, hyperbilirubinemia (32/50), and hypercholesterolemia (24/43). Ultrasonographic abnormalities of the hepatobiliary system were seen in 84% of cases. On histopathology, 53 of 54 affected dogs had neutrophilic cholangitis (NC) or cholangiohepatitis, whereas 1 dog had lymphocytic cholangitis. Most cases (42/54) were chronic. Evidence of concurrent biliary disease (46.2%) and biliary tract obstruction (42.6%) was common. Seventeen of 36 biliary and 11 of 25 liver cultures were positive for bacterial growth; Escherichia coli and Enterococcus spp. were most common. Median patient survival was 671 days (95% confidence interval [CI]: 114–1,426). On Cox regression, dogs that did not have a cholecystectomy performed had a 2.1 greater hazard for death (P = 0.037; 95% CI: 1.0–4.3) compared to cholecystectomized dogs. Dogs >13 years old had a 5.0 greater hazard for death (P = 0.001; 95% CI: 1.9–13.2) compared to younger dogs.Conclusions and Clinical SignificanceChronic NC or cholangiohepatitis was most common. Cholecystitis and biliary tract obstruction often occurred in conjunction with cholangitis. Cholecystectomized dogs had decreased risk of death; thus, cholecystectomy may improve patient outcome.

Erythrodermic psoriasis with associated sterile neutrophilic cholangitis

Erythrodermic psoriasis with associated sterile neutrophilic cholangitis

Acute Alpha-Naphthylisothiocyanate-induced Liver Toxicity in Germfree and Conventional Male Rats.

Differences in the responses of conventional and germfree male Sprague-Dawley rats to acute injury induced by alpha-naphthylisothiocyanate (ANIT), a well-characterized biliary epithelial toxicant, were evaluated. Conventional and germfree rats were dosed once orally with 50 mg/kg of ANIT or corn oil alone and serially sacrificed daily for the next 3 days. Germfree rats treated with ANIT tended to have greater increases in virtually all liver and biliary-related analytes compared with conventional rats treated with ANIT; however, significant differences were found only in a few of these analytes including increased bile acids on day 3, total bilirubin on day 4, glutamate dehydrogenase (GLDH) on day 3, and reduced paraoxonase 1 (PON1) on days 2 and 3. Histologic differences between the conventional and germfree rats were modest, but most pronounced on day 2 (24-hr post dosing). Based on subjective scoring, biliary necrosis, neutrophilic cholangitis, and portal tract edema were more severe in germfree rats at 24 hr post dosing compared with conventional rats. Biliary epithelial replication did not differ between treated groups, however. Overall, germfree rats had a modestly greater level of biliary tract injury based on subjective histologic scoring and clinical chemistry measurements following an acute exposure to the well-characterized biliary toxin, ANIT; however, the difference between the ANIT-treated germfree and conventional groups was modest and most evident only within the first day following exposure. These findings suggest that the microbiome did not significantly affect ANIT-induced acute biliary tract injury in the conditions of this study.

Psoriasis and the liver: problems, causes and course.

Psoriasis patients have a higher risk of liver abnormalities such as non-alcoholic fatty liver disease (NAFLD), drug-induced hepatitis, alcoholic hepatitis and neutrophilic cholangitis, than the general population. Associated liver disease limits therapeutic options and necessitates careful monitoring. The aim of the study was to identify liver problems in psoriasis patients and to investigate the underlying causes as well as their course. The files of 518 psoriasis patients were retrospectively reviewed. Among these, 393 patients with relevant laboratory data were analysed for liver enzymes and their relation to the known risk factors for liver disease (obesity, diabetes mellitus, alcohol consumption, hepatotoxic medications, dyslipidemia, psoriatic arthritis and infectious hepatitis). Among 393 patients, 24% and 0.8% developed liver enzyme abnormalities and cirrhosis, respectively. The most common factors associated with pathological liver enzymes were drugs (57%) and NAFLD (22%). Other rare causes were alcoholic hepatitis, viral hepatitis, neutrophilic cholangitis, autoimmune hepatitis and toxic hepatitis due to herbal therapy. Drug-induced liver enzyme abnormalities were reversible whereas in patients with NAFLD transaminases tended to fluctuate. One patient with herbal medicine-related cirrhosis died of sepsis. Liver enzyme abnormalities are common in psoriasis patients and are mostly associated with drugs and NAFLD. Although most cases can be managed by avoiding hepatotoxic medications and close follow up, severe consequences like cirrhosis may develop.

Cholangiosepsis Caused by Neutrophilic Cholangitis in Plaque Psoriasis

Psoriasis is a common inflammatory skin disease with many comorbid conditions. We present a 37-year-old male patient with a history of plaque psoriasis, status febrilis, violent umbilical pain, elevated inflammatory markers and liver parameters. Blood cultures were tested positive for E. coli. Diagnostic findings indicated that mechanical icterus and cholangiosepsis in the context of neutrophilic cholangitis were caused by inflammatory stenosis. Neutrophilic cholangitis is often found in combination with skin diseases with intense cutaneous infiltration with polymorphonuclear leucocytes and peripherial blood neutrophilia. Interleukin-8 may play a role in the pathogenesis of neutrophilic cholangitis occurring in patients with psoriasis [1]. We showed that complications of psoriasis can also occur at unusual locations. To date no case of neutrophilic cholangitis as an elicitor of cholangiosepsis has been reported.

Common bile duct duplication: A case report

A 9-year-old female neutered domestic shorthair cat was presented with a history of polyphagia, weight loss and inappropriate urination. Clinical examination revealed jaundice and a mid-cranial abdominal mass. Further investigations revealed a large extra-hepatic cyst originating from the biliary tract (choledochal cyst). Concurrent chronic, active neutrophilic cholangitis and chronic lymphoplasmacytic pancreatitis were also noted. Surgical drainage, subtotal resection and omentalisation of the cyst, along with supportive medical management, were successful in relieving the clinical signs.

Evaluation of fluorescence in situ hybridization for the detection of bacteria in feline inflammatory liver disease.

The etiopathogenesis of feline inflammatory liver disease (ILD) is unclear. Therefore, we sought to determine the presence and distribution of bacteria within the livers of cats with ILD using eubacterial fluorescence in situ hybridization (FISH). Histopathology from 39 cats with ILD and 19 with histologically normal livers (C) were classified using World Small Animal Veterinary Association guidelines. Hepatic sections were examined by 16 and 23S ribosomal RNA FISH. Antibodies against cytokeratins and factor VIIIa were used to distinguish bile ducts and vascular structures. Histopathologic findings included non-specific reactive hepatitis (12), neutrophilic cholangitis (NC; 12), lymphocytic cholangitis (seven), cholestasis/obstruction (three), probable lymphoma (three) and acute hepatitis (two). Bacteria were observed in 21/39 ILD and 3/19 C (P = 0.0054). In 8/39 ILD and 2/19 C bacteria were restricted to the outer liver capsule (P = 0.29) and may represent contaminants. The prevalence of intrahepatic bacteria was higher (P = 0.008) in ILD (13/31) than C (1/17). Bacteria in ILD were more frequently (P <0.0001) localized to portal vessels, venous sinusoids and parenchyma (12/13) than bile duct (1/13). Bacterial colonization was highest in Escherichia coli-positive NC cats. Concurrent non-hepatic disease, predominantly pancreatic and intestinal (8/10 cats biopsied), was present in all 13 cats with intrahepatic bacteria. Bacterial culture was positive (predominantly E coli and Enterococcus species) in 11/23 (48%) samples, and concurred with FISH in 15/23 cases. The presence of intrahepatic bacteria in 13/31 (41%) cats with ILD suggests a role in etiopathogenesis. The distribution of bacteria within the liver supports the possibility of colonization via either enteric translocation or hematogenous seeding.

Neutrophilic cholangitis in psoriasis vulgaris and psoriatic arthritis

Neutrophilic cholangitis in psoriasis vulgaris and psoriatic arthritis

Feline cholangitis: a necropsy study of 44 cats (1986–2008)

Forty-four cats diagnosed with moderate to severe cholangitis at necropsy are described. The population comprised 0.86% of all feline necropsies performed during the 22-year study period. Liver specimens were classified as acute neutrophilic cholangitis (ANC), chronic neutrophilic cholangitis (CNC), lymphocytic cholangitis (LC) or chronic cholangitis associated with liver fluke infestation (CC) based on the World Small Animal Veterinary Association (WSAVA) classification scheme. ANC (seven) and CNC (33) comprised the majority of cases. In contrast to previous descriptions, overlap was seen in clinical findings between ANC and CNC subtypes. Results suggest that liver enzyme activity may not predict degree of inflammation. Severity of inflammation varied between liver sections in individual cats, underscoring the need to obtain biopsy samples from multiple sites. Inflammatory bowel disease (50%), pancreatitis (60%), or both (32%) commonly accompanied cholagitis. We conclude that cholangitis is not a common cause of feline mortality. Most cats that succumb to cholangitis have ANC or CNC, and concurrent disease contributes to death in many.

Primary sclerosing cholangitis in children and adolescents: a clinicopathologic study with a proposal of criteria for early diagnosis

INTRODUCTION: Primary sclerosing cholangitis (PSC) has been increasingly diagnosed among children and adolescents due to better recognition of clinical, imaging and pathological features. Thus more patients are diagnosed at a younger age due to imaging and sensitivity optimization. OBJECTIVE: Early liver histopathological (LH) changes are not well described and PSC is not commonly recognized before typical bile duct changes occur on cholangiography (CG). Currently, CG is considered gold standard for adults but nothing is known for early diagnosis in the pediatric age group (0- 20 years old). METHODS: We reviewed clinical history, LH and CG from 47 children and adolescents with PSC (35 males, mean age 13 years old). Forty-three out of 47 patients had been through LH examination from whom 33 had also undergone CG. A clinicopathological correlation was performed. RESULTS: LH showed active neutrophilic cholangitis in 19 patients, moderate neutrophilic pericholangitis in nine, dystrophic changes in the bile duct in eight, and concentric periductal fibrosis in 24 patients. Abnormal CG was found in 24 out of 33 patients and nine had normal results. Eleven out of these 24 patients had abnormal histology before abnormal CG and four patients had abnormal CG before histology. Data of two out of 24 patients were insufficient for correlation and 11 out of 24 had both abnormal liver histology and abnormal imaging findings. CONCLUSION: Our study emphasizes that even when CG is normal, PSC should be exclusively diagnosed by liver biopsy, hence cholangiography being unnecessary. Chronic portal inflammation, neutrophilic pericholangitis, periductal sclerosis and "onion skinning" are characteristic histopathological findings. Neutrophilic pericholangitis may be subtle and easily overlooked in early disease, leading to strong suspicion of PSC.

Recurrent childhood von Zumbusch pustular psoriasis associated with neutrophilic cholangitis, successfully controled with etanercept

Recurrent childhood von Zumbusch pustular psoriasis associated with neutrophilic cholangitis, successfully controled with etanercept

A dramatic response to a single dose of infliximab as rescue therapy in acute generalized pustular psoriasis of von Zumbusch associated with a neutrophilic cholangitis

Generalized pustular psoriasis of von Zumbusch is an unstable, inflammatory form of psoriasis, with the hallmark of neutrophil infiltration in cutaneous as well as extracutaneous lesions. It is often recalcitrant, making treatment difficult. Tumour necrosis factor-alpha antagonists including infliximab have been used with success in treating recalcitrant cases. We report a case of a 48-year-old Chinese female patient with a long-standing history of poorly controlled generalized pustular psoriasis which was resistant to multiple therapies. During a severe flare, a single dose of infliximab resulted in rapid clearing of cutaneous lesions, together with resolution of liver function abnormalities that are likely secondary to neutrophilic cholangitis. Subsequent maintenance therapy with acitretin allowed remission of pustular disease for 7 months. This demonstrates the efficacy of single-dose infliximab for both cutaneous lesions and systemic hepatic involvement in generalized pustular psoriasis.

Infliximab Induced Hepatitis with Autoimmune Features

Purpose: 37-year-old man with Ulcerative Colitis since 11 years, on infliximab for last 8 months, presented with increasing fatigue, myalgia and fever. Laboratory evaluation revealed elevated liver enzymes (Table 1). Patient had extensive work up including viral serologies, fungal etiologies, iron studies, alpha-1 antitrypsin and ceruloplasmin levels which were non diagnostic. Antinuclear antibody (ANA) Titers were 1:640 (homogenous pattern). Antidouble stranded DNA (Ds DNA) was positive and complement levels were low. Anti-smith antibody, smooth muscle antibody, F-actin antibody, anti-neutrophilic cytoplasmic antibodies(ANCA), SS-A and SS-B were all negative. Colonoscopy showed severe inflammation in descending colon, sigmoid colon and rectum with multiple ulcerations and inflammatory exudate. Biopsies showed active colitis with no dysplasia. MRCP showed periportal inflammatory changes and pericholecystic edema. Liver biopsy showed predominantly portal hepatitis with bridging necrosis, neutrophilic cholangitis and increased eosinophils suggestive of drug induced Hepatitis most likely secondary to infliximab. After discontinuation of infliximab, liver enzymes trended down by 10 weeks and were normal after 5 months. ANA and Ds-DNA remained elevated. Although generally safe and well tolerated, tumor necrosis factor-α (TNF-α) inhibitors are associated with the induction of autoantibodies in a dose and duration dependent manner. Autoimmune hepatitis (AIH) is a very rare adverse side effect of infliximab. To date only 6 cases of AIH have been reported. Pathogenesis of infliximab induced hepatitis is unclear. One hypothesis could be an increase of apoptotic particles which represent a reservoir of autoantigens. Nucleosomes which represent core chromatin are major auto antigens released during cell death. One group has shown higher levels of circulating nucleosomes following infliximab infusions. The accumulation of nucleosomes could possibly enhance development of auto antibodies in subjects with appropriate genetic backgrounds. Another theory is that TNF-α blockade interferes with the normal cytotoxic T-lymphocyte suppression of auto (self)-reactive B cell production. Genetic predisposition is also thought to be important, with HLA DR3 and DR4 alleles being associated with Type 1 AIH. Withdrawal of infliximab is the standard therapy for TNF-α induced hepatitis. Average clinical recovery after removal of offending agent is 10 months. As TNF-a inhibitors are being used more frequently for management of inflammatory bowel disease, we need to remember AIH as a potential consequence of TNF inhibitor therapy.Table 1