Tuesday, January 26, 2016

President's Message January 2016

Dear Friends and Colleagues,

I hope everyone has had a great holiday season and are well into 2016. Please see the HPHS website www.hanspopperhepatopathologysociety.org for the latest edition of The Literature Watch. This free series is posted every two months. The Interesting Case series is also posted four times each year.

The deadline to submit trainees’ USCAP abstracts for the HPHS awards is Feb. 27. Every year the HPHS recognizes trainees deemed to have submitted the winning abstracts to the Annual USCAP conferences. The winning abstract is awarded a cash prize while the first and second runners up are also recognized at the HPHS Annual meeting during the USCAP conference, which this year will be in Seattle, WA.

We look forward to seeing you at our next HPHS business meeting in Seattle in March!

Isabel Fiel, M.D.
President, Hans Popper Hepatopathology Society

Interesting Case January 2016

Clinical History

A 51 years old woman was referred for liver transplantation on account of end-stage primary biliary cirrhosis (PBC). She had presented with variceal bleeding outside. Her liver was found to be enlarged but she had normal INR and albumin although bilirubin was slightly elevated at 1.8 mg/dL (31 μmol/L). She however had other features of portal hypertension including splenomegaly and low platelets (78,000/µL).  Serologically she was AMA positive (high titer), IgM was elevated but IgG and IgA were normal. Liver enzymes were AST 12 U/L, ALT 10 U/L, and ALP 200 U/L (on Urso treatment). Ultrasound confirmed nodular and cirrhotic liver. She was listed for transplantation as end-stage PBC.

She successfully underwent living related liver transplantation. The explanted liver weighed 1233 gm and appeared vaguely nodular but not cirrhotic. Cut sections revealed no mass lesions. Micrographs from the explanted liver are shown.










Rhodanin copper stain


Liver Explant Microscopic Findings

The explant showed a nodular liver with areas of sinusoidal dilatation, and occasional incomplete septae, but no evidence of cirrhosis. Rare florid ducts of PBC are present but there is mild ductopenia that came down to approximately just 20% of the terminal bile ducts; the larger bile ducts appear normal as are most of the small/terminal bile ducts. Several small portal tracts however have increased portal and occasionally periportal fibrosis and no visible portal veins. The larger portal tracts often have small portal veins when compared with the corresponding hepatic artery or bile duct, with thickening of the veins walls (obliterative portal venopathy). Reticulin stain demonstrates nodularity not bordered by fibrous septae, the edge of the nodules having compressed reticulin fibers (NRH). Sections from the hilum demonstrate major but non-occlusive portal vein thrombus.

Diagnosis

Non-cirrhotic portal hypertension from a combination of nodular regenerative hyperplasia (NRH), portal vein thrombosis, and obliterative portal venopathy (OPV) in a patient transplanted for Primary Biliary Cirrhosis


Major Learning Points

  1. Portal hypertension in patients with normal liver function (albumin, bilirubin, INR) should raise the possibility of non-cirrhotic cause.
  2. Primary biliary cirrhosis and other chronic biliary diseases could cause portal hypertension from NRH and/or obliterative portal venopathy without being cirrhotic or “end-stage”.
  3. Liver explant examination is important to verify cause of liver disease as this has a significant implication on post-transplant course and management.

Discussion

Portal hypertension is a common end-stage presentation of many chronic liver diseases the likelihood of which parallels severity of cirrhosis. As such patients with Childs-Pugh C cirrhosis have worse manifestations of liver failure from cirrhosis than Childs-Pugh A and B patients. Symptomatic cirrhosis is typically accompanied by abnormal liver function tests (albumin, INR/coagulation parameters, and bilirubin) although liver enzymes could remain normal or near normal even in advanced cirrhotics. Portal hypertension with normal liver function could occur in compensated cirrhosis but normal function accompanied by symptoms of portal hypertension like variceal bleeding in this patient, should raise the possibility that portal hypertension may not be arising from cirrhosis. This is because decompensated cirrhosis is a reflection of failing ability of liver parenchyma to optimally function. Whereas most (not all) cases of non-cirrhotic portal hypertension with normal hepatic mass are less likely to manifest as functional abnormality. In such cases features of PH are limited to vascular shuntings (varices and sometimes encephalopathy) and splenomegaly (including low platelets).

Also liver vasculature could be secondarily affected by chronic biliary diseases as exemplified by this case. For this reason, and for several years, PBC for example has been recognized as a cause of NRH and associated with OPV. It has been postulated that repeated pre-sinusoidal injury possibly from PBC-associated portal inflammation could secondarily cause inflammation and loss of small portal veins over time, leading to NRH. [Kew MC, et al. Gut. 1971;12(10):830-4]. In this case and possibly in combination with other factors, the direct effect of chronic portal vein injury is also manifested as obliterative portal venopathy, OPV. 

OPV, (also called hepato-portal sclerosis, HPS), is an entity in which portal hypertension resulted from injury to and thickening of the wall of large and intermediate intrahepatic portal veins and obliteration of the smaller veins (Nayak NC & Ramalingaswami V. Arch Pathol 1969; 87: 359-69; Aggarwal S et al. Dig Dis Sci 2013; 58: 2767-76.).  It could complicate a long list of diseases including PBC as well as many systemic and organ-specific immunologic diseases (Lee H, Rehman AU, Fiel MI 2015 J Pathol Transl Med Epub ahead of print), for which reason an immunologic basis has been proposed. Another association with the OPV is thrombophilia (Hillaire S, et al. Gut 2002; 51: 275), with some OPV patients secondarily developing secondary portal vein thrombosis, also seen in the present case. 

It would therefore appear that the findings in the presented case are part the same process that started with vascular (portal vein) injury in the context of PBC leading to OPV, which in turn gave rise to NRH (Wanless IR, et al. Medicine (Baltimore) 1980; 59: 367-79.); and ultimately portal hypertension. The development of large portal vein thrombosis could be from portal hypertension since this patient has so far not been found to have a thrombophilic state. She is now 3 years post-transplant and doing excellently well.  

Case contributed by:
Oyedele Adeyi, M.D.
University of Toronto

References:

  1. Abraham SC, Kamath PS, Eghtesad B, Demetris AJ, Krasinskas AM. Liver transplantation in precirrhotic biliary tract disease: Portal hypertension is frequently associated with nodular regenerative hyperplasia and obliterative portal venopathy. Am J Surg Pathol. 2006;30(11):1454-61
  2. Kew MC, Varma RR, Dos Santos HA, Scheuer PJ, Sherlock S. Portal hypertension in primary biliary cirrhosis. Gut. 1971;12(10):830-4
  3. Nayak NC, Ramalingaswami V. Obliterative portal venopathy of the liver: associated with so-called idiopathic portal hypertension or tropical splenomegaly. Arch Pathol 1969; 87: 359-69.
  4. Aggarwal S, Fiel MI, Schiano TD. Obliterative portal venopathy: a clinical and histopathological review. Dig Dis Sci 2013; 58: 2767-76.
  5. Lee H, Rehman AU, Fiel MI. Idiopathic Noncirrhotic Portal Hypertension: An Appraisal. J Pathol Transl Med. 2015 Nov  [Epub ahead of print]
  6. Hillaire S, Bonte E, Denninger MH, et al. Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients. Gut 2002; 51: 275-80.
  7. Wanless IR, Godwin TA, Allen F, Feder A. Nodular regenerative hyperplasia of the liver in hematologic disorders: a possible response to obliterative portal venopathy. A morphometric study of nine cases with an hypothesis on the pathogenesis. Medicine (Baltimore) 1980; 59: 367-79.

In Memoriam Professor Sir Roderick N. M. MacSween, BSc, MBChB, MD, 1935-2015

Roderick Norman McIver MacSween, (or Roddy, as most of us called him), was born in 1935 in the Western Isles of Scotland (Kinloch, Isle of Lewis) the son of a manse and a native Gaelic speaker who learned English when he went to school.  He attended Glasgow University, graduating with a BSc with Honours in Physiology in 1956 and MB ChB in 1959.  He chose Pathology as a career and in 1963, and joined the Western Infirmary, Glasgow.   He became a lecturer in 1965 and after gaining his MRCPath in 1967, a post-graduate fellowship allowed him to study at Colorado University Medical Center in Denver from January 1968 to December 1969, where he further developed his interest in iron metabolism.  On his return to the Western Infirmary in 1970, he was awarded a Wellcome Senior Research Fellowship and working with Professor John Anderson, earned an MD with Honours in 1973 with a thesis on “Clinico-Pathological and Immunological Studies in Liver Disease”.  Rising rapidly through the ranks of Senior Lecturer, Reader and Titular Professor, he succeeded John Anderson as the sixth holder of the Chair of Pathology at the Western Infirmary and Head of Department in 1984, positions he held until his retirement in 1999. 

In 1985 he was elected Fellow of the Royal Society of Edinburgh and served on its Council from 1992-1995. His served as Vice-President of the Royal College of Pathologists from 1995-1996 and as President from 1996-1999. He also served as Editor of IAP journal “Histopathology” from 1985-96, President of the British Division of the IAP, and Chairman of the British Association for Study of the Liver.  His leadership skills were also recognized in other medical disciplines where he served as Chairman of the Academy of Medical Royal Colleges from 1998-2000.  He retired in 1999 and became Sir Roddy when he was knighted in 2000 for services to Medicine and Pathology.  A member of the General Medical Council from 1999-2003, his numerous charitable works included serving as Chairman of Tenovus Scotland, Chairman of the Medical Advisory Committee of the Children’s Liver Foundation and as a Committee Member of the British Lung Foundation (Scotland). He was also Chair of the Unrelated Liver Transplant Regulatory Authority and President of the Royal Philosophical Society of Glasgow.  

Professor Sir Roddy MacSween (Roddy) was a skilled interpreter of liver biopsies with a national and international reputation and a world-wide referral practice.  In 1978 he was invited to join a unique distinguished international hepatopathology group known as the Gnomes, the name applied to them by Dame Sheila Sherlock (London) after their first meeting in Zurich.  She claimed that the liver Gnomes, like the financial Gnomes of Zurich, were manipulating interpretation and classification in hepatopathology.  Roddy had many other accomplishments, including prestigious lectureships, numerous publications, and significant editorial duties.  Perhaps he is most widely recognized by our society for his editorship of Pathology of the Liver, the first edition with Peter Anthony and Peter Scheuer as co-editors, with further editions in 1987, 1994 and 2002.  The textbook’s comprehensive nature by this time was reflected in a review which stated “If it’s not in MacSween, it’s not in the liver”.  He retired as an editor for the 2007 fifth edition, but his successors retitled the book MacSween’s Pathology of the Liver in order to carry on the significance of the name of the founder.  The 6th edition was published in 2012, and the 7th edition is in preparation.   This authoritative textbook rapidly became and has remained the definitive textbook for liver pathology around the world.

He married Marjory Brown, a fellow medical student (and later, dermatologist), in 1961.  Together, they enjoyed their family (children Ruth and Gordon, and grandchildren), and loved to travel and visit friends worldwide, as well as play golf.  

Throughout his career he was beloved by his students, residents, and other mentees as an outstanding teacher with endless energy and enthusiasm, and a caring mentor.  As many of you know, he formed friendships easily.  A continual stream of visitors from around the world spent time with him learning the art of liver biopsy interpretation.  No matter how busy he was, he always made time to view his set of case slides with each at a double-headed microscope, and he would bade them farewell with the words “thank you for paying us the complement of coming here to study”.  Many of these visitors have become leaders in liver pathology worldwide.

On his death, many remember him as one of the giants and luminaries of liver pathology, and praise him for the great legacy he left liver pathology for future generations.  Their memories are also filled with appreciation for his enthusiasm and ability in teaching, his encouragement to many to pursue their studies, and most significantly, his great warmth and generous, kind spirit that put all at ease, no matter what their personal status or relationship to him.  

He will be greatly missed as a friend, colleague, and mentor, but we rejoice that his legacy and memory will live on the hearts and minds of pathologists worldwide, and we thank you, Sir Roddy, for inspiring us in so many ways.

In loving memory,

Linda Ferrell, MD
Emerita Professor, University of California San Francisco

Monday, January 25, 2016

Journal Watch November-December 2015

Clinical Gastroenterology and Hepatology, Nov-Dec 2015


The art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond 
James H. Lewis  Clin Gastroenterol Hepatol. 2015;13:2173-2189.

In this review article, the author summarizes the key advances in the clinical diagnosis and management of idiosyncratic drug induced liver injury (DILI) during the last decade. It is estimated that about half of the cases of acute liver failure (ALF) occurring annually in the United States are due to DILI, especially from acetaminophen (40%), but also other drugs (11%) such as herbal compounds and dietary supplements (HDS). The classic host risk factors for DILI are age (>65 years), gender (female), use of alcohol and obesity. Daily drug doses of 50-100mg are more hepatotoxic than <10mg.  Three main biochemical injury patterns have been recognized: hepatocellular, cholestatic and mixed. The diagnosis of DILI is clinically challenging as DILI can mimic all known causes of acute and chronic liver diseases. Liver biopsy findings may be supportive for DILI but most helpful in excluding other possible causes. Recently, substantial progresses have been made in identifying predictive biomarkers (microRNA 122, high mobility group box-1 and keratin 18) and genetic risk factors (HLA and cytochrome phenotypic alterations) for DILI.  Preventing DILI is limited to liver associated biochemistry (ALT) monitoring and restricting access to certain drugs.  Liver transplantation remains an important treatment procedure for irreversible ALF. The first published guidelines on the diagnosis and management of DILI has been offered by the American college of Gastroenterology. In addition, a LiverTox Web site (livertox.nih.gov) has been launched recently.

Journal of Hepatology, Nov-Dec 2015


Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation
Miltiadous O, Sia D et al. Journal of Hepatology 2015; 63: 1368-1377. 

Liver transplantation (LT) is an effective treatment option for patients with HCC within Milan criteria. The concept of a modest expansion beyond the Milan criteria has been proposed without gaining global acceptance. The current study explored the possibility of using gene signatures to identify patients with HCC beyond Milan criteria who nevertheless may have acceptable outcomes with LT. 132 patients with HCC beyond Milan criteria underwent LT at two medical centers were included in the study. Explant tumors were analyzed for genomic signatures and Immunohistochemical markers, and then correlated with patient outcome. At a median follow up of 88 months, the 5-year survival and recurrent rates were 57% and 35%, respectively. In the multivariate analysis, S2 gene signature (HR = 3.18, p = 0.001), tumor diameter >5 cm (HR=5.06, p<0.001), and outside up-to-7 rule (HR=2.50, p= 0.002) were independently associated with 5 year survival. CK19 (HR = 2.91, p = 0.001), tumor diameter >5 cm (HR=3.37, p=0.023) and satellites (HR = 2.98, p <0.001) were independent predictors of recurrence. Combination of progenitor signatures (CK19 and S2) improves prediction both OS and recurrence.  Patients with one and/or both signatures had a 45% 5-year OS and 53% recurrence vs. 67% 5-year OS and 19% recurrence when neither signature was present. These results suggested that the gene signatures of progenitor cell (CK19/S2) may be potential makers for stratifying patients with HCC in high and low risk for both recurrence and survival.

Histopathology, Nov-Dec 2015


CAMTA1 is a useful immunohistochemical marker for diagnosing epithelioid haemangioendothelioma. 
Shibuya R, Atsuji A, Eisuke S, Hiroshi H, Kei Y, Masanori H. Histopathology 2015;67(6):827-835.
And
Molecular characterization of epithelioid haemangioendotheliomas identifies novel WWTR1–CAMTA1 fusion variants. 
Patel NR, Salim AA, Sayeed H, Sarabia SF, et al. Histopathology 2015;67(5):699-708.

Epithelioid hemangioendothelioma is an intermediate grade endothelial neoplasm that could be primary in or metastatic to the liver. The WWTR1–CAMTA1 translocation leading to CAMTA-1 overexpression had been found to be very specific for majority of EHE, while the remaining lesions carry the alternative YAP1–TFE3 translocation. Until now the way to demonstrate these translocations had been by PCR for the fusion gene transcript and/or FISH methods. However the first study, Shibuya R et al report successful use of CAMTA1 antibody by immunohistochemistry with a sensitivity of 87.5% and specificity of 99.6%. Only one false positive case in a breast ductal carcinoma was reported.
The second study Patel NR et al reported successful use of RT-PCR and direct gene sequencing in epithelioid hemangioendothelioma, majority of their cases arising from or involving the liver.  In addition to detecting the WWTR1–CAMTA1 transcript in 14 of 18 cases, 4 cases, when directly sequenced also showed novel in-frame fusion transcripts. Only 1 of 18 cases demonstrated YAP1–TFE3 fusion transcript and this case also showed strong nuclear TFE3 immunostain. Other degrees of TFE3 stain were found in 5 other cases, 3 of which had no YAP1–TFE3 fusion transcript; the remaining 2 failed RT-PCR. The use of TFE3 immunostain required a specific (strong nuclear) staining pattern for specificity in cases harboring the YAP1–TFE3 translocation.

Journal of Gastroenterology and Hepatology, Nov-Dec 2015


Intimate association of visceral obesity with non-alcoholic fatty liver disease in healthy Asians: A case-control study.
Ha Y et al. Journal of Gastroenterology and Hepatology. Nov. 2015, 30 (11):1666-72.

The study was to identify factors associated with non-alcoholic fatty liver disease (NAFLD) in Asian subjects. Potential living liver donors without hepatic steatosis (< 5%: n = 1353, group 1) were considered as controls, and subjects with mild (5-33%: n = 724, group 2) and moderate/severe (> 33%: n = 116, group 3) steatosis were defined as study groups. Age and gender were matched, which resulted in 83 matched subjects in each of the three groups. The area of abdominal (visceral and subcutaneous) fat was measured in all subjects by unenhanced computed tomography. Serum AST, ALT, gamma-glutamyltranspeptidase, total cholesterol and triglyceride levels, and visceral fat amount were found directly correlated with the grade of steatosis, while high-density lipoprotein cholesterol levels were inversely correlated. In a multivariate model, visceral fat amount was significantly correlated with both mild and moderate/severe NAFLD groups (P < 0.05). Body mass index (BMI), ALT, and subcutaneous fat were significant predictors of only moderate/severe NAFLD group (P < 0.05).The findings indicate that visceral adiposity makes non-obese subjects more susceptible to NAFLD, compared with subcutaneous fat and BMI.

American Journal of Pathology, Nov-Dec 2015


Mice with Hepatic Loss of the Desmosomal Protein ϒ-catenin are Prone to Cholestatic Injury and Chemical Carcinogenesis
Zhou L et al.  Am J of Pathol 2015;185:3274-3289.

The role of β-catenin as an important component of the adherens junction and canonical Wnt signaling is fairly well understood. In this paper, however, the authors explore the role of ϒ-catenin, an important component of desmosomes, in liver pathobiology. This study used conditional knockout (KO) mice, bile duct ligation (BDL) and a model of chemical carcinogenesis (CC, diethylnitrosamine). KO mice at baseline showed a significant change in the desmosome composition, although the desmosome structure and function were maintained. However, KO mice subjected to BDL showed increased injury and fibrosis, and KO mice subjected to CC showed enhanced tumorigenesis via Wnt signaling. The authors conclude that ϒ-catenin appears to have a tumor suppressor function which could have therapeutic implications.

Hepatology, Nov-Dec 2015


CX3CR1 is a Gatekeeper for Intestinal Barrier Integrity in Mice: Limiting Steatohepatitis by Maintaining Intestinal Homeostasis
Schneider KM et al. Hepatology 2015;62:1405-1416.

CX3CR1 is G protein-coupled chemokine receptor expressed on macrophages that is involved in maintaining intestinal homeostasis in addition to playing a role in several of the manifestations of the metabolic syndrome. Since diet induced intestinal dysbiosis is a driver for NASH, the authors studied wild type and CX3CR1 deficient mice exposed to 2 diet-induced models of NASH (high fat diet or MCD diet). CX3CR1 protected mice from excessive liver steatosis and inflammation, as well as systemic glucose intolerance. Lack of CX3CR1 altered the intestinal microbiota composition, was linked to an impaired mucosal barrier and a greater amount of bacterial translocation. Nonabsorbable antibiotic treatment showed a marked improvement in steatohepatitis. The authors conclude microbiota-mediated activation of the innate immune responses through CX3CR1 is crucial for controlling NASH progression. With regards to the gut-liver axis, CX3CR1 is an essential gatekeeper and maintains the intestinal mucosal barrier.

A Novel Noninvasive Diagnostic Method for Nonalcoholic Steatohepatitis Using Two Glycobiomarkers
Kamada Y et al. Hepatology 2015;1433-1443.

Two glycobiomarkers, fucosylated haptoglobin (Fuc-Hpt) and Mac-2 binding protein (Mac2bp), were used to predict the degree of NASH ballooning and fibrosis, respectively. By combining the 2 serum markers together and using logistic regression analysis, the authors developed a prediction model for the diagnosis of NASH. This model was then validated using 382 biopsy proven NAFLD patients. Furthermore, the utility of this model was tested in a larger population of 803 NAFLD patients undergoing medical health checkups. The authors conclude that this serologic test-based glycobiomarker model is a novel NASH diagnostic modality that could replace liver biopsy.

Association of Nonalcoholic Fatty Liver Disease with Hepatocellular Carcinoma in the United States from 2004 to 2009
Younossi ZM et al. Hepatology 2015;62:1723-1730.

The SEER registries from 2004-2009 along with Medicare-linkage files and ICD codes were used to assess the prevalence and mortality of patients with NALFD-HCC in comparison with other chronic liver diseases such as HCV, HBV and alcoholic liver disease. Almost 5,000 cases of HCC and almost 15,000 controls without HCC were identified for statistical analysis. During the 6 year period NAFLD-HCC showed a 9% annual increase. NAFLD-HCC patients were older, had shorter survival time, more heart disease and were more likely to die from their primary liver cancer (all P < 0.0001). In multivariate analysis, NAFLD increased the risk of 1-year mortality. The authors conclude that NAFLD is becoming a major cause of HCC in the United States and that NAFLD-HCC is associated with a shorter survival time, more advanced stage and lower possibility of receiving a liver transplant.

Prospective Evaluation of the Diagnostic Accuracy of Hepatic Copper Content as Determined Using the Entire Core of a Liver Biopsy Sample
Yang Xu et al. Hepatology 2015;62:1731-1741.

Hepatic copper determination is an important tool for establishing the diagnosis of Wilson disease (WD), however, the methodology has not been standardized, the diagnostic accuracy prospectively validated and the optimum cut off value established. This is a prospective study of 3,350 consecutive patients who underwent core liver biopsy; 691 of those patients underwent liver biopsy with two passes, of which 178 were diagnosed with WD using a clinical and laboratory values based WD score (e.g., neuropsychiatric symptoms, Kayser-Fleischer rings, serum ceruloplasmin, urinary copper excretion, ATP7B mutation analysis etc) in combination with clinical follow up. ROC analysis supported a hepatic copper content cut off of 209 µg/g dry weight for the diagnosis of WD, if PBC and PSC have been excluded, instead of the two commonly cited but widely divergent cut off values of 250 µg/g dry weight and 75 µg/g dry weight. Copper deposition is unevenly distributed in the liver parenchyma and sample size is very important. Stringent study methodology was used to conclude that two passes of liver biopsy should be performed and a dedicated entire core of liver should be used for copper determination. The authors reiterate that histochemical staining is often negative when copper is diffusely distributed in the hepatocyte cytoplasm and histochemistry is more accurate only when copper is sequestered into lysosomes.

Human Pathology, November 2015


Immunohistochemical characterization of the regenerative compartment in biliary atresia: a comparison between Kasai procedure and transplant cases.
Kuo FY, et al. Hum Pathol. 2015;46(11):1633-9. 

This study examines immunohistochemical expression of CD56, CK7 and CK19 in relatively early biliary atresia (BA) patients (those undergoing Kasai procedure, n=24) vs, those with relatively late disease (those undergoing liver transplantation, n=64). The degree of ductular reaction and CK19 staining was similar on both groups. CD56 staining was seen significantly more often in liver transplant group. The authors suggest that the regenerative compartment shows more expansion in BA patients undergoing transplant and that there is more active regeneration in livers with advanced-stage BA.

Diagnostic value of maspin in distinguishing adenocarcinoma from benign biliary epithelium on endoscopic bile duct biopsy.
Chen L, et al. Hum Pathol. 2015;46(11):1647-54. 

The authors have shown in their previous studies that immunohistochemistry for insulin-like growth factor II mRNA-binding protein 3, S100P, and the von Hippel-Lindau gene product
(pVHL) can help to distinguish benign vs. malignant biliary epithelium. This study examines maspin (a serine protease inhibitor) expression by immunohistochemistry in 134 endoscopic bile duct biopsies (adenocarcinoma 45, atypical 31, and benign 58). Positive staining with maspin was seen more often in malignant cases, with diffuse nuclear and cytoplasmic staining of intermediate to strong intensity. Maspin was positive in 67% of atypical cases, which was consistent with an adenocarcinoma diagnosis made on follow-up. Maspin+/S100P+/pVHL- phenotype was present in 75% of malignant cases, while no benign biopsy showed this pattern.

Gastroenterology, Nov-Dec 2015


Liver Histology and Clinical Trials for Nonalcoholic Steatohepatitis-Perspectives From 2 Pathologists
Kleiner DE, Bedossa P. Gastroenterology. 2015 Nov;149(6):1305-8.

This is a very thoughtful commentary on various aspects of steatohepatitis by two experienced and widely respected hepatopathologists. The authors highlight the following points and diagnostic challenges:
(1) NAFL and NASH are considered as a dichotomous concept from the viewpoint of clinical trials. This is an oversimplification and does not allow proper categorization of cases with intermediate features. The NASH CRN has used the term ‘borderline NASH’ for these cases. For binary analysis in clinical trials, the NASH CRN has included these cases with cases showing definite NASH. The author state that further work is needed to clarify the utility of a more detailed histologic classification of NAFLD.
(2) Since binary classification into NAFL and NASH somewhat artificial, the authors advocate the concept that NAFLD is a chronic liver disease with a continuous spectrum, both in terms of disease activity and fibrosis.
(3)Histologic activity in NAFLD is reflected by features that are used to diagnose NASH: ballooning and lobular inflammation). European FLIP (Fatty Liver Inhibition of Progression) consortium has proposed the SAF (steatosis, activity, fibrosis) score. This involves semiquantitative evaluation of steatosis, activity (ballooning, inflammation), and fibrosis. This score does not include steatosis as part of disease activity, which is different from the NAFLD activity score (NAS).
(4) Fibrosis is a histologic marker of disease stage, and is more strongly associated with adverse clinical outcomes than histologic activity. Fibrosis has much higher reproducibility between pathologists compared to disease activity, and is an excellent indicator of adequacy of the biopsy (recommended 2 cm core using at least a 16-G needle). Hence regression of fibrosis may be the best marker to test drug efficacy. However, fibrosis regression is likely to take more time compared to markers of disease activity, and need a more generous biopsy. Despite these challenges, fibrosis regression is a goal that can be achieved for clinical trials as has been demonstrated in the FLINT study over a 72-week period. An expanded semiquantitative fibrosis staging system (from 0 to 6, similar to Ishak scheme for chronic viral hepatitis) or morphometric techniques may help in assessing fibrosis regression in shorter trials.
(5) Defining resolution of NASH is difficult, but is often required for clinical trials. The authors suggest that this should be defined as loss of ballooning (to a score of 0), with at least a 1-point decrement in lobular inflammation, without worsening of fibrosis.

Extrahepatic Morbidity and Mortality of Chronic Hepatitis C
Negro F, et al. Gastroenterology. 2015;149(6):1345-60. 

Extrahepatic manifestations associated with chronic hepatitis C includes mixed cryoglobulinemia which can manifest as cutaneous/visceral vasculitis, glomerulonephritis and B-cell lymphoma. Insulin resistance, diabetes, and atherosclerosis are common in hepatitis C cases and can lead to increased cardiovascular disease. Fatigue and cognitive impairment can also occur as part of neurological manifestations. The multisystem disease may be related to endocrine disturbances, viral replication in extrahepatic tissue, or an aberrant systemic immune reaction. Treatment with interferon alfa and ribavirin can improve the extrahepatic effects and the use of new interferon-free regimens may lead to greater improvements in extrahepatic manifestations. It is possible that extrahepatic manifestations can become an indication for treatment even if significant liver disease is not present.

American Journal Gastroenterology, Nov-Dec 2015


Changing Nomenclature for PBC: From 'Cirrhosis' to 'Cholangitis'
Beuers U, Gershwin ME, Gish RG, et al. Am J Gastroenterol. 2015 Nov;110(11):1536-8.

In this position paper sponsored by the European Association for the Study of Liver Diseases of the authors describe the history of the nomenclature of primary biliary cirrhosis and propose an alternative name given that many patients with this disease do not present with cirrhosis.  A survey was sent out to expert in the fields and “primary biliary cholangitis” had the broadest support.  The authors contend that this change will have critical implications for patients by removing the stigma of cirrhosis.

Saturday, November 21, 2015

Journal Watch September - October 2015

Modern Pathology, Sept-Oct 2015


Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases
Schlitter AM, Jang KT, Klöppel G, et al. Mod Pathol. 2015 Sep;28(9):1249-64.

Intraductal tubulopapillary neoplasm of the bile ducts is the biliary counterpart of pancreatic intraductal tubulopapillary neoplasm. In this report, 20 cases were studied focusing on the clinicopathologic features and molecular profiles. The tumors were predominantly intrahepatic (70%) with mean size of 6.9 cm. The neoplasms were immunoreactive for MUC1 (80%) and MUC6 (30%). 80% of the lesions were associated with invasive carcinoma. The overall survival was favorable: 1 year 100%, and 5 years 90%. Molecular studies showed low prevalence of alterations of common oncogenic signaling pathways in this tumor.

American Journal of Pathology, Sept-Oct 2015


Hepatic Progenitor Cells in Action: Liver Regeneration or Fibrosis?
Kaur S, Siddiqui H and Bhat MH. Am J Pathol. 2015 Sept;185:2342-2350.

This is a nice review of the current knowledge regarding hepatic progenitor cells and their role in both hepatic fibrosis and hepatic regeneration during liver injury.

Human Pathology, Sept-Oct 2015


Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.
Liau JY, et al. Hum Pathol. 2015;46(9):1360-6.

Alternative lengthening of telomeres (ALT) can enable endless cancer cell replication. ALT has been associated with inactivation of α-thalassemia/mental retardation syndrome X-linked (ATRX) and death domain-associated (DAXX) protein. This study focused on ATRX/DAXX expression and ALT status in malignant vascular tumors. Loss of ATRX expression was observed in 21% (16/77) of the primary angiosarcomas and 9% (1/11) of epithelioid hemangioendotheliomas. DAXX expression was intact in all but 2 ATRX-deficient angiosarcomas. Telomere-specific FISH was ALT-positive in 28% (17/61) of the primary angiosarcomas and was highly associated with loss of ATRX expression, as 26/28 ALT-positive angiosarcomas were ATRX deficient. Primary liver angiosarcomas were ATRX deficient (8/13) and/or ALT positive (8/12), while none of the secondary angiosarcomas showed these findings. The only ATRX-deficient epithelioid hemangioendothelioma was positive for ALT. The study concludes that ALT and loss of ATRX expression are frequently observed in hepatic angiosarcomas.

Advance in Anatomic Pathology, Sept-Oct 2015


Update on the Liver Imaging Reporting and Data System: What the Pathologist Needs to Know
Tang A. et al . Advance in Anatomic Pathology. 2015, 22(5): 314-322.

Hepatocellular carcinoma (HCC) is frequently diagnosed noninvasively with imaging methods. In 2008, the American College of Radiology supported the development of the Liver Imaging Reporting and Data System (LI-RADS) for standardized terminology and reporting for the diagnosis of HCC. This article reviews the basic concepts of LI-RADS, emphasizing aspects that are most relevant to pathologists, including the categories, diagnostic algorithm, major features, and ancillary features for the diagnosis of HCC. Importantly, LI-RADS is designed to diagnose progressed HCC with high specificity and modest sensitivity, but not designed to detect early HCC and so have limited sensitivity for such lesions. Another relevant point to pathologists is that imaging detection of small (<1 cm) nodules is restricted. For these reasons LI-RADS require lesions to be 1 cm or greater for the noninvasive diagnosis of HCC.

American Journal of Clinical Pathology, Sept-Oct 2015


The Significance of Autoantibody Changes Over Time in Primary Biliary Cirrhosis
Tana MM et al. Am J Clin Pathol  2015;144:601-606

The significance of autoantibodies (AMA, ANA) in PBC disease stage and prognosis is unclear.  In this article, the authors tested serial serum samples from patients with PBC for autoantibodies, and correlated the levels of autoantibodies with clinical, laboratory, and histologic outcomes.  145 serum samples from 27 PBC patients were studied. The medium follow up time was 20 years. In the initial serum samples, the positivity for autoantibodies was:  AMA (93%), ANA (100%), SSA-52 (48%), sp100 (22%), gp210 (22%), centromere (19%), SS-A (15%), chromatin (4%), SS-B (4%), RNA polymerase III (0%), SLA (0%), Scl-70 (0%), respectively. Most antibody levels did not change significantly over time except for sp100 (a specific type of ANA). Furthermore, there was a significant inverse relationship between change in sp100 autoantibody level and fibrosis score on serial liver biopsy specimens. The data suggests that changing sp100 level despite treatment might indicate disease progression.

Histopathology, Sept-Oct 2015


Hypoxia after transarterial chemoembolization may trigger a progenitor cell phenotype in hepatocellular carcinoma.
Lai JP, Conley A, Knudsen BS, Guindi M. Histopathology. 2015 Oct;67(4):442-50.

This study tested the expression of three markers in recurrent lesions of hepatocellular carcinoma (HCC) treated by TACE (Transcatheter Arterial Chemoembolization). The three markers are carbonic anhydrase IX (CAIX) [marker of hypoxia] as well as the cholangiocytic/progenitor markers cytokeratin (CK19) and epithelial cell adhesion molecule (EpCAM) [as markers of aggressive HCC biology]. The authors operated on the hypothesis that these markers were expressed in post-TACE hypoxic areas, and by implication contributed to a selection of aggressive clone that recurred. Out of 40 recurrent tumors, 19 expressed CAIX (versus 2/17 in untreated controls). They found that only recurrent tumors expressing CAIX co-expressed CK19 (6 of 19 tumors) and EpCAM (7/19), although EpCAM and CK19 were only co-expressed in 3 of 7 tumors that expressed EpCAM. This finding concluded that TACE paradoxically selected for aggressive tumor phenotype by causing hypoxia, which in turn “may trigger the expression of proteins that are normally associated with cholangiocytic/progenitor cell.

Journal of Gastroenterology and Hepatology, Sept-Oct 2015


Clinical outcomes of cryptogenic compared with non-cryptogenic cirrhosis: A retrospective cohort study
Mohammed OK. et al. Journal of Gastroenterology and Hepatology, 2015, 30(9):1423-8.

The consequences of cryptogenic versus non-cryptogenic cirrhosis were compared in a large, single academic center over 5-year duration. The study included 301 patients with cirrhosis (94 cryptogenic and 207 non-cryptogenic). Compared with non-cryptogenic cirrhosis, patients with cryptogenic cirrhosis were older (mean age 66.4 vs 60.7 years), had more females (43.6% vs 26.6%), had less disease severity (Child–Pugh C 8.5% vs 15.9%), and had a higher prevalence of the metabolic syndrome (83% vs 51.2%). Cryptogenic cirrhosis is associated with a longer duration of hospitalization compared with non-cryptogenic cirrhosis at an early stage of the disease. This difference is due to a greater burden of non-liver-related complications in the former. Kaplan–Meier survival analysis showed no significant differences in survival between both types of cirrhosis for all grades of severity.

Hepatology, Sept-Oct 2015


The Significance of Nonobstuctive Sinusoidal Dilation of the Liver: Impaired Portal Perfusion or Inflammatory Reaction Syndrome.
Marzano C, Cazals-Hatem D, Rautou PE et al. Hepatology. 2015 Sept;62:956-963.

This very nice review highlights conditions associated with nonobstructive sinusoidal dilation and discusses the pathogenic roles played by interleukin-6, Notch1 and VEGF.

Hepatic Lipid Droplet Biology: Getting to the Root of Fatty Liver.
Mashek DG, Khan SA, Sathyanarayan A et al. . Hepatology. 2015 Sept;62:964-967.

This review highlights recent advances in our knowledge of lipid droplet biology and associated liver disease.

The Severity of Steatosis Influences Liver Stiffness Measurement in Patients with Nonalcoholic Fatty Liver Disease.
Petta S, Maida M, Macaluso FS, et al. Hepatology. 2015 Oct;62:1101-1110.

In many chronic liver diseases (CLDs), the risk of liver-related and overall mortality, as well as therapeutic decision-making, is linked to the fibrosis stage.  Methods for noninvasive and rapidly performed point-of-care testing are being sought, especially for highly prevalent CLDs such as NAFLD. Vibration-controlled transient elastography (VCTE) by Fibroscan, which uses liver stiffness measurement (LSM) as a surrogate of liver fibrosis, has been validated in viral hepatitis. The authors of this paper assessed the impact of liver steatosis severity on LSM values and transient elastography accuracy in a 253 patient cohort of biopsy proven NAFLD. They report that among patients with low amounts of fibrosis (F0-F1 and F0-F2), median LSM values were significantly higher in subjects with severe steatosis (>66% on liver biopsy) and that about one-third of the subjects with BMI >30 kg/m2 had an unreliable LSM. They conclude that in patients with severe steatosis, LSM might overestimate liver fibrosis.

Salivary Microbiota Reflects Changes in Gut Microbiota in Cirrhosis with Hepatic Encephalopathy.
Bajaj JS, Betrapally NS, Hylemon PB et al. Hepatology 2015 Oct;62:1260-2171.

It has become well established that patients with cirrhosis have enteric dysbiosis and that an altered gut microbiome is associated with systemic inflammation and cirrhosis decompensation. The aim of this study was to evaluate the oral microbiome in cirrhosis and compare it with the stool microbiome. Ninety-day liver-related hospitalizations were also noted. The cohort consisted of 102 patients (43 with previous hepatic encephalopathy [HE]) and 32 age-matched controls. Thirty-eight patients were hospitalized within 90 days and these patients salivary dysbiosis was significantly worse and predicted this outcome independent of cirrhosis severity. Salivary inflammation was studied in an additional 86 age-matched subjects (43 controls and 43 patients with cirrhosis. Significantly higher inflammatory markers (interleukin-6 and interleukin-1β, secretory IgA and lower lysozyme and histatins 1 and 5 were found in the cirrhotic patients. The authors conclude that dysbiosis is present in both stool and saliva in cirrhosis patients and cirrhotic patients have impaired salivary defenses and worse inflammation. Salivary dysbiosis was greater in patients with cirrhosis who developed 90-day hospitalizations. These findings may reflect a global mucosal-immune interface dysfunction in cirrhosis.

Gut, Sept-Oct 2015


Impact of common risk factors of fibrosis progression in chronic hepatitis C.
Rueger S, Bochud P-Y, Dufour J-F. et al.  Gut.  2015;64:1605-1615

The authors follow 1461 Swiss patients with chronic HCV hepatitis who had at least 1 biopsy and an estimated date of infection.  The factors that were associated with accelerated fibrosis (defined as ≥0.13 Metavir fibrosis units per year) were identified.  Older age at infection, male sex, genotype 3, and route of infection (intravenous drug use) were associated with accelerated progression.  Age at infection was the strongest contributor to accelerated fibrosis followed by route of infection.  This was confirmed in other cohorts and by a meta-analysis.  Diabetes, BMI, and HIV infection were not associated with accelerated fibrosis progression.  Three single nucleotide polymorphisms were also associated with fibrosis progression.  Although the important factors that favor fibrosis progression are not modifiable the knowledge of these factors may help prioritize treatment of HCV infection.

Gastroenterology, Sept-Oct 2015


Liver Stem Cells: Experimental Findings and Implications for Human Liver Disease.
Michalopoulos GK, Khan Z. Gastroenterology. 2015;149(4):876-82.

Nice review of histologic and experimental aspects of liver stem cells. The review emphasizes that the potential of hepatocytes to rescue cholangiocytes is widely accepted, while the possibility of cholangiocytes giving rise to liver progenitor cells and hepatocytes is not supported by experimental studies and remains controversial. Some studies in mice suggest that cholangiocyte to hepatocyte transdifferentiation can occur and depends on inhibition of hepatocyte proliferation The ability of hepatocytes and cholangiocytes to serve as potential stem cells for each other may help prevent more effectively than tissue-specific stem cells.

Genetic Landscape and Biomarkers of Hepatocellular Carcinoma.
Zucman-Rossi J, et al. Gastroenterology. 2015;149(5):1226-1239.

Comprehensive review on the genetics of hepatocellular carcinoma (HCC) including common abnormalities such as TERT promoter mutation (60%), TP53 and CTNNB1 mutations (25-30%), chromosomal aberrations [DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), homozygous deletions in chromosome 9 (CDKN2A)], and less frequently involved genes (AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2),. The potential for specific therapeutic approaches targeting the involved pathways is discussed. Based on genomic profiling data, 2 major molecular clusters (proliferation and nonproliferation) of HCC are described.

Clinical Gastroenterology and Hepatology, Sept-Oct 2015


Association Between Endogenous Sex Hormones and Liver Fat in a Multiethnic Study of Atherosclerosis
Lazo M et al. Clin Gastroenterol Hepatol. 2015;13(9):1686-1693
Metabolic abnormalities are considered the major cause for Nonalcoholic fatty liver disease (NAFLD). In previous studies with small sample size, the association between circulating sex hormones and metabolic abnormalities has been reported. The current study is however the first large cohort study to evaluate the association between circulating sex hormones (testosterone, estradiol, dehydroepiandrosterone, and sex hormone binding globulin (SHBG)) and fatty liver; included are 2835 postmenopausal women and 2899 men aged 45-84 years.. The data indicated that 1) higher levels of estradiol are associated with fatty liver in both men and women independent of demographic, anthropometric, and cardiometabolic risk factors. 2) Postmenopausal women with high level of bioavailable testosterone are at greater risk for fatty liver than women with low levels. 3) In men, higher levels of SHBG are associated with reduced risk for fatty liver.

Journal of Hepatology, September 2015


Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis.
Lanthier N et al.  Journal of Hepatology 2015; 63: 609-621.

Alcoholic hepatitis (AH) is a distinct manifestation of alcoholic liver disease that is associated with significant morbidity and mortality. Many scoring systems have been developed to assess the disease severity of AH. However, there is no ideal prognostic scoring system for clinical use. In this study, Lanthier et al. investigated the association of liver progenitor cell (LPC), macrophage and gene expression patterns with prognosis of AH. Liver biopsies obtained from AH and abstinent alcoholic cirrhotic patients were studied by immunohistochemistry and microarray gene expression. The related cytokines in serum from AH and control patients were also measured. CD68+ macrophages, CK7+/ki-67- and CK7+/Ki67+ LPCs were increased in AH compared to abstinent cirrhosis. In the follow-up study, patients with significant expansion of liver macrophages and a high number of proliferating hepatocytes as well as proliferating LPCs showed a better outcome. In addition, when compared to controls, an obvious upregulation of genes involved in cell cycle, mitosis and proliferation pathways, as well as a high expression of SPINK1 was found in AH patients. The study suggested that increased proliferating hepatocytes and LPCs, high expression of certain genes, and macrophage expansion in biopsy samples might act as markers for favorable outcome. The data from the gene expression study provided important information to help identifying the potential targets for AH treatment.

Prepared by:
Rish Pai, MD, PhD; Mayo Clinic Arizona
Sanjay Kakar, MD; University of California, San Francisco
Cindy Guy, MD; Duke University
Wenqing Cao, MD; New York University
Jingmei Lin, MD, PhD; Indiana University
Oyedele Adeyi, MD; University of Toronto
Charles Lassman, MD; University of California, Los Angeles

Journals Reviewed
American Journal of Surgical Pathology, Modern Pathology, Histopathology, Human Pathology, American Journal of Clinical Pathology, Journal of Pathology, Archives of Pathology and Laboratory Medicine, Advances in Anatomic Pathology, Hepatology, Journal of Hepatology, Liver Transplantation, Gastroenterology, Gut, Clinical Gastroenterology and Hepatology, Journal of Gastroenterology and Hepatology, American Journal of Gastroenterology, Nature

Tuesday, October 27, 2015

President's Message October 2015

Dear Friends and Colleagues,

I hope everyone has had a great start to this academic year. Our fall edition of newsletter is here for your reviewing pleasure. 

I would like to bring to your attention a new feature of our HPHS website, “Journal Watch” put together by diligent work of the members of the education committee. “Journal Watch” is a summary of the recent and seminal liver pathology related papers published in reputable journals. I will encourage all of you to refer to this new feature of our website. This is a great way for all of us to stay up to date with the literature. Please see the website www.hanspopperhepatopathologysociety.org for the latest edition.

Additionally, I would like to strongly encourage members to consider submitting your USCAP abstracts for our annual “Hans Popper Hepatopathology Society Trainee Award”. The award will be presented during our HPHS business meeting in Seattle in March 2016. 

Sincerely,

Isabel Fiel, M.D.
President, Hans Popper Hepatopathology Society

Interesting Case October 2015

Clinical History:

An obese sixty year old gentleman with a history of GERD and hypertension presented to an emergency room with repeated bouts of sharp unremitting right upper quadrant pain over a one year period.  Imaging findings during clinical workup (see below) revealed changes concerning for gallbladder adenocarcinoma.  A biliary stent was placed, and the patient was referred to a tertiary center for further management.  Exploratory laparotomy demonstrated an indurated gallbladder which was densely adherent to the porta hepatis and the interface between segments 4B and 5.  A cholecystectomy and resection of the aforementioned liver segments was performed for presumed adenocarcinoma of the gallbladder.  

Labs:

At initial evaluation: AST, 474; ALT, 358; alkaline phosphatase, 268; INR, 1.1

Imaging:

CT scan demonstrated heterogeneity of the fundus of the gallbladder and multiple benign hepatic cysts.  MRI and MRCP showed and thickened gallbladder wall with dilation and beading of the biliary tree but no evidence of common bile duct stones.  The clinical differential included malignancy, adenomyomatosis, inflammation, and infection.  

Cholecystectomy and Liver Segmentectomy Findings:

Sections of the gallbladder demonstrated a marked chronic inflammatory infiltrate with numerous germinal centers and plasma cells involving the lamina propria and muscularis mucosa, with focal involvement of the submucosa (Figures 1&2).   The submucosa was fibrotic.  Immunohistochemistry demonstrated polytypic plasma cells with clusters of up to 40 IgG4 positive plasma cells per 40x field (Figure 3). The superficial gallbladder wall demonstrated scattered IgG4 plasma cells and the deeper, more fibrotic portions of the gallbladder wall demonstrated prominent clusters of IgG4 positive plasma cells. The surface epithelium showed mild reactive changes but no dysplasia.  Sections of the liver segmentectomy showed normal architecture. Portal areas contained mild to moderate chronic inflammatory infiltrates.  A few portal areas demonstrated prominent clusters of lymphocytes.  Many portal areas did not contain a portal vein branch and in one septal portal area there was fibrous obliteration of the vein (Figure 4, white arrow).  The parenchyma demonstrated atrophy of zone 3 hepatocytes (blue arrow) compatible with portal vein compromise (Figure 5).

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Diagnosis: 

Chronic cholecystitis consistent with IgG4 sclerosing disease with sclerosing portal venopathy.
No dysplasia or carcinoma.

Discussion:

Immunoglobulin G4 (IgG4)-related disease is a fibroinflammatory condition that is characterized by tumor-like swelling of involved organs, due to a dense lymphoplasmacytic infiltrate with numerous IgG4 positive plasma cells, a “storiform” pattern of fibrosis, eosinophilia, obliterative phlebitis, and in most cases elevated serum IgG4 concentrations above the upper limit of normal (>135 ng/dL) (N Engl J Med. 2012 Feb;366(6):539-51).  IgG4-related disease has been described in essentially every organ system, including the biliary tree.  It typically occurs in middle-aged men, especially in association with conditions such as type 1 (IgG4-related) autoimmune pancreatitis (AIP), IgG4-related tubulointerstitial nephritis, and retroperitoneal fibrosis.  However, the proportion of female patients  appear to be significantly higher than in men with respect to head and neck manifestations of the disease, such as IgG4-related sialadenitis and IgG4-related ophthalmic disease (Am J Surg Pathol. 2010;34(12):1812).  

IgG4-related sclerosing cholangitis is the second most common manifestation of the disease, second only to type 1 autoimmune pancreatitis (AIP).  The percentage of patients with AIP who have extrahepatic bile duct involvement is estimated to be between 71-100%, and rarely occurs in the absence of pancreatitis (Curr Opin Rheumatol. 2011;23(1):57).  It is imperative to distinguish IgG4-related cholangitis from primary sclerosing cholangitis since the former is typically responsive to steroid therapy (Gastroenterology. 2008 Mar;134(3):706-15).  Inflammatory bowel disease and cholangiocarcinoma, both of which are associated with primary sclerosing cholangitis, has not been reported in patients with IgG4-related sclerosing cholangitis (Curr Opin Gastroenterol. 2008;24(3):389).  The presence of clinical manifestations in extra-biliary organs, histomorphological findings such as IgG4 positive plasma cells, storiform interstitial fibrosis, and responsiveness to steroids, can all help differentiate  these two entities.  

IgG4-related sclerosing cholangitis in the absence of AIP is rare, and as in the current case, can mimic extrahepatic cholangiocarcinoma.  It is seen primarily in middle to older age men.  A recent study compared material from patients with IgG4-related sclerosing cholangitis without AIP, to those with IgG4-related sclerosing cholangitis and AIP, and to those with extrahepatic cholangiocarcinoma, primary sclerosing cholangitis, and secondary sclerosing cholangitis.  The histomorphologic features that helped distinguish IgG4-related sclerosing cholangitis from these other entities include a marked degree of bile duct injury, higher percentage of lymphoid follicle formation, a higher percentage of perineuritis, as well as a more diffuse and dense lymphoplasmacytic infiltrate.  The authors also found that the presence of more than 50 IgG4-positive plasma cells per high power field in a biopsy specimen was sufficient to exclude cholangiocarcinoma. Therefore biopsy specimens with fewer than 50 IgG4  positive plasma cells  did not adequately exclude the presence of unsampled cholangiocarcinoma (Scand. J. Gastroenterol. 2015 Apr;50(4):447-453) 

Case Contributed by:
Ramir Arcega, MD and Charles Lassman, MD, Ph.D.
UCLA David Geffen School of Medicine 

Friday, September 18, 2015

Journal Watch July-August 2015

American Journal of Gastroenterology, July-August 2015


Long-Term Prognostic Significance of Persisting Histological Activity Despite Biochemical Remission in Autoimmune Hepatitis.
Harpreet K et al.  Am J Gastro 2015;2110:993-9

The clinical significance of persistent histologic activity despite biochemical remission in patients with autoimmune hepatitis is unknown.  The authors studied 120 patients with autoimmune hepatitis who received immunosuppression and underwent liver biopsy at least 6 months after sustained biochemical remission (normal ALT and serum globulins).  Despite having biochemical remission, 55/120 (46%) had persistent histologic activity (defined as HAI ≥4).  No differences were seen in patients who achieved histologic remission compared to those who did not with regard to pretreatment clinical, laboratory, or histologic parameters.  No differences in treatment and time to biochemical remission was observed between these two groups.  However, serum ALT and AST were lower in those who achieved histologic remission.  The presence of HAI ≥4 on follow-up biopsy was associated with decreased fibrosis regression (60% versus 32%, p=0.004).  Finally, patients who did not achieve histologic remission had reduced transplant-free and overall survival.

American Journal of Surgical Pathology, July-August 2015


One Hundred Thirteen Consecutive Transgastric Liver Biopsies for Hepatic Parenchymal Diseases: A Single-institution Study.
Nakanishi, Y et al.  Am J Surg Pathol 2015;39:968-76

In this study, the authors present their results from 113 transgastric liver biopsies performed at a single institution (using QuickCore needle, ProCore needle, and Flex needle).  The transgastric biopsies were compared to 100 percutaneous and 100 transjugular biopsies.  The main reason for obtaining transgastric liver biopsies was assessment of fatty liver disease (43%) followed by elevated LFTs (25%).  In contrast percutaneous liver biopsies were performed mainly for grading and staging chronic hepatitis (45%).  The main indication for transjugular liver biopsy was to evaluate for cirrhosis.  In contrast to transjugular and percutaneous biopsies, transgastric biopsies were often quite fragmented and contained >10 tissue fragments with a median fragment length of 4 mm.  Most transgastric biopsies yielded less complete portal tracts; although biopsies obtained from the Flex needle performed as well as transjugular and percutaneous biopsies. Using the QuickCore neede a median of 2 complete portal tracts was obtained whereas 9 and 12 portal tracts were obtained using the ProCore and Flex needle respectively.  Transgastric biopsies were less likely to be adequate for staging and diagnosis as only 42%, 75% and 85% of the QuickCore, ProCore and Flex needle biopsies, respectively were deemed.  All transgastric biopsies contained gastric mucosa.

Ipilimumab-associated Hepatitis: Clinicopathologic Characterization in a Series of 11 Cases.
Johncilla, M et al.  Am J Surg Pathol 2015;39:1075-84

Ipilimumab is a monoclonal antibody directed against CTLA4 on T-cells and is most often used to treat metastatic melanoma.  Ipilimumab has been associated with a wide variety of immune-mediated side effects including colitis, enteritis, pancreatitis, nephritis and generalized lymphadenopathy.  The authors study 11 cases of ipilimumab associated hepatitis.  No patient had preexisting liver disease and 10 patients had normal LFTs before ipilimumab treatment.  Two patterns of hepatitis were observed, panlobular hepatitis and zone 3 hepatitis.  Three patients with panlobular hepatitis also had zone 3 necrosis and central vein endotheliitis was commonly seen. The inflammatory cell infiltrate consisted mostly of lymphocytes and histiocytic aggregates whereas plasma cells were usually rare, although in 3 patients they were more prominent.  In one patient steatohepatitis was identified and another showed cholangitis.  Discontinuation of ipilimumab resulted in improvement of LFTs in all patients.  All patients were also treated with steroids.

Archives of Pathology and Laboratory Medicine, July-August 2015


Comparison of 5 Immunohistochemical Markers of Hepatocellular Differentiation for the Diagnosis of Hepatocellular Carcinoma.
Nguyen, T et al Arch Pathol Lab Med.  2014;139:1028-34

The authors compare the efficacy of 5 hepatocellular markers (arginase-1, hep par1, glypican-3, polyclonal CEA, and bile salt export pump transporter) in the diagnosis of hepatocellular carcinoma.  The authors included well differentiated, moderately differentiated and poorly differentiated hepatocellular carcinoma.  Of the 79 HCC cases, only 1 case failed to stain with arginase-1 (a poorly differentiated HCC).  Importantly, hep-par1 failed to stain 14/39 poorly differentiated HCC.  Polyclonal CEA and BSEP also performed poorly in high-grade tumors.  Gylpican 3 staining increased with increasing tumor grade.  Arginase 1 and glypican 3 immunohistochemistry may be most useful in the diagnosis of poorly differentiated hepatocellular carcinoma.

Clinical Gastroenterology and Hepatology, July-August 2015


Identification and Characterization of Cefazolin-induced Liver Injury.
Alqahtani SA et al. Clin Gastroenterol Hepatol. 2015;13(7):1328-1336

Cefazolin is a commonly used first generation Cephalosporins, for which drug induced liver injury (DILI) is generally considered rare. A recent ongoing prospective study from the United States, Drug Induced Liver Injury Network (DILIN), identified 19 out of 1212 (2%) patients with DILI attributed to Cefazolin, making Cefazolin the sixth most common single agent in the data set.  Cefazolin induced liver injury has a latency period of about 20 days (1-3 weeks), and shows a self-limited moderate to severe clinical course characterized by a cholestatic biochemical and histologic pattern. The study also identified 14 more patients with DILI attributed to other Cephalosporins, a few of them were associated with severe injury and death. For the first time, the authors describe the clinical presentations, laboratory tests and histopathology of cephazolin induced DILI, and identify Cephalosporins as a relative common cause of antibiotic-associated liver injury.

Gut, July-August 2015


A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration.
King Y et al.  Gut 2015;64:1296-1302

Cirrhosis due to HCV is increasing.  While eradication of the virus decreases the risk of disease progression, it does not eliminate the risk.  In a prior study, the authors developed a 186-gene expression panel that can risk stratify patients with HCV.  In this study the authors implemented the 186-gene signature using an FDA-approved clinical diagnostic assay platform.  The authors of this study developed a prognostic gene expression signature in an attempt to risk stratify HCV patients with cirrhosis.  Using RNA isolated from FFPE samples, the authors validate this gene signature using a training cohort.  A 145 patient validation cohort was appropriately risk stratified using this gene panel as the high-risk group experienced more frequent hepatic decompensation (HR=7.36), overall death (HR=3.57), and liver-related death (HR=6.49).  Importantly, the prognostic association remained statistically significant in Child-Turcotte-Pugh class A patients (n = 121) indicating that it will be useful in patients with “early cirrhosis”.

Gastroenterology, July-August 2015


Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.
Angulo P, et al. Gastroenterology. 2015;149(2):389-397.

Editorial: The Hierarchical Model of NAFLD: Prognostic Significance of Histologic Features in NASH.
Loomba R, et al. Gastroenterology. 2015;149(2):278-81.

This study examines prognostic significance of histologic features in 619 NAFLD cases. Older age, diabetes, current smoking and presence of fibrosis (as well as stage of fibrosis) were associated with death or liver transplantation. Ballooning and portal inflammation were significant associations, but not in multivariate analysis. Sage 3 and stage 4 fibrosis were the only features associated with liver-related events (defined as variceal bleeding, HCC, liver-related death, liver transplant). Steatosis grade, lobular inflammation and NAFLD score were not associated with overall mortality or liver-related events.

Hepatology, May 2015


Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
Ekstedt M, et al. Hepatology. 2015;61(5):1547-54.

The outcome in 229 biopsy-proven NAFLD with mean available follow-up of 26.4 years was compared to a reference population. NAFLD patients had higher risk of cardiovascular disease, hepatocellular carcinoma, infections and cirrhosis. NAFLD patients with stage 3 and stage 4 fibrosis had increased mortality, but not those with no fibrosis or lower stage of fibrosis.

Journal of Gastroenterology and Hepatology, July-August 2015


Usefulness of endoscopic ultrasound-guided sampling using core biopsy needle as a percutaneous biopsy rescue for diagnosis of solid liver mass: Combined histological-cytological analysis.
Lee YN. Et al. J Gastroenterology and Hepatology. July, 2015; 30(7):1161-1166.

In this study, the diagnostic accuracy of EUS-guided fine needle biopsy (EUS-FNB) was studied. Twenty-one patients underwent EUS-FNB after the failure of a percutaneous biopsy for liver solid mass. The median number of needle passes was 2.0 (range, 1-5). On-site cytology and cytology with Papanicolaou stain showed malignancy in 16 (76.2%) and 17 patients (81.0%), respectively. In histology with H&E stain, 19 patients (90.5%) were diagnosed malignancy and optimal to IHC stain. The overall diagnostic accuracy for malignancy and specific tumor type were 90.5% and 85.7%, respectively. No complications were seen. In summary, EUS-FNB with core biopsy needle may be helpful in the management of patients who are unable to diagnose using percutaneous liver biopsy.

Journal of Hepatology, July-August 2015


Targeting cyclin dependent kinase 5 in hepatocellular carcinoma – A novel therapeutic approach.
Ehrlich SM et al.  Journal of Hepatology 2015; 63: 102-13.

Recently, dysregulation of cyclin dependent kinase 5 (Cdk5) has been linked to malignancy, including cancers of the prostate, pancreas, thyroid, lung, cervix, myeloma, and breast. In the study, the role of Cdk5 in HCC progression was investigated. Increased expression of Cdk5 and its activator P35 were seen in HCC compared to normal liver tissues. Overexpression of Cdk5 promoted HCC cell growth in vitro. Genetic (siRNA and shRNA) or pharmacologic (roscovitine) inhibition of Cdk5 expression reduced HCC cell proliferation and tumor growth in a xenograft mouse model. Furthermore, HCC cell line and xenografts were treated with CDK5 inhibition plus DNA-damage-inducing chemotherapeutics to examine the effect on cancer cell proliferation and tumor growth. Data showed that down regulation of Cdk5 expression enhanced the sensitivity of various DNA damaging agents in HCC. The study suggested that CDK5 might be a novel treatment target, and combination of CDK5 inhibition and DNA-damaging agent could serve as an effective therapeutic approach for HCC.

Breast tumor kinase/protein tyrosine kinase 6 (Brk/PTK6) activity in normal and neoplastic biliary epithelia.
Mizuguchi Y et al. Journal of Hepatology 2015; 63:399-407

In this article, using immunohistochemistry, the authors found BRK protein was expressed at low level in normal intrahepatic bile ducts. The expression of BRK was significantly higher in CC cell lines and a majority of CC compared to normal tissues. High expression of BRK in CC was associated with extrahepatic location and well differentiation. Studies in vitro revealed BRK co-localized with EGFR and ErbB2/neu, and promoted tumor growth. Knock down BRK by siRNA significantly reduced tumor cell proliferation. The data indicated the important role of BRK in HCC progression, suggesting that BRK might serve as a target for HCC treatment.

Modern Pathology, July-August 2015


The liver in heart failure: a biopsy and explant series of the histopathologic and laboratory findings with a particular focus on pre-cardiac transplant evaluation.
Louie CY., et al. Modern Pathology July 31st, 2015 (28):932-943

Liver biopsies are commonly obtained as part of the work up before heart transplantation in patients with longstanding right heart failure, particularly if ascites, abnormal liver function tests or abnormal abdominal imaging are noted as part of the pre-transplant evaluation. In these cases, the liver biopsy findings may be used to further risk stratify patients for isolated heart or combined heart and liver transplantation. Thus, it is important to be able to correlate the histologic changes with post-transplant outcomes.  In this report, the pathologic and clinical findings in liver explants from six patients who underwent combined heart-liver transplantation and preoperative liver biopsies from 21 patients who underwent heart transplantation without simultaneous liver transplantation were studied. The changes related to chronic passive congestion were staged as follows: stage 0-no fibrosis; stage I-pericellular fibrosis; stage II-bridging fibrosis; and stage III-regenerative nodules. Thirteen biopsies showed bridging fibrosis in 13 and 6 had regenerative nodules. Fifteen patients were alive at 1 year post transplant. Only three patients had a postoperative course that was characterized by signs and symptoms of chronic liver disease. Pre-transplant liver biopsies from these 3 patients all showed at least stage II fibrosis. These 3 patients survived for 3, 6, and 10 months after cardiac transplant. It appears that the presence of bridging fibrosis was not significantly associated with postoperative survival (P=0.336) or postoperative liver failure (P=0.257). In conclusion, patients with bridging fibrosis may still be considered viable candidates for isolated heart transplantation.

Infiltrative (sinusoidal) and hepatitic patterns of injury in acute cellular rejection in liver
allograft with clinical implications
Siddiqui A. et al. Modern Pathology July 31st, 2015 (28) 1275–1281

Two patterns of acute cellular rejection (ACR), sinusoidal infiltrative and hepatitic, were described in this study. Twenty-eight cases of ACR with rejection activity index 5 or above were included. Among them, 15 (54%) had typical, 6 (21%) hepatitic and 7 (25%) sinusoidal infiltrative ACR. Sinusoidal infiltrative ACR occurred later (124 versus 50 days; P=0.032) and had a higher rise in baseline AST compared with the conventional one (289 vs 109 U/l; P=0.046). Only one out of seven patients with sinusoidal infiltrative ACR (14% versus 40% in typical ACR) failed Solu-Medrol boluses and required thymoglobulin. Patients with hepatitic ACR had similar AST (P=0.12) but higher bilirubinemia than typical one (160 vs 35 mol/l; P=0.039) and required thymoglobulin in four out of six (67% vs 40%) instances. Patients with sinusoidal infiltrative ACR had higher AST than the typical one but better Solu-Medrol response compared with both the typical and hepatic ACR.

Nature July-August 2015


Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver.
Wang B, et al. Nature 2015 Aug 13;524(7564):180-185.

This report revolutionizes how we think about liver regeneration and hepatocytes renewal and shifts emphasis away from the Canals of Hering to the perivenular zone. The authors, using the wnt-responsive Axin2 gene lineage-traced renewal of hepatocytes by diploid, Axin2-expressing, cells in the perivenular zone of mice liver. This study demonstrate the presence of diploid Axin2 cells ONLY around hepatic veins, and that these cells differ from hepatocytes which are almost always non-diploid (having 4N-32N polyploidy). The authors surmised that being polyploid was a disadvantage to hepatocytes’ ability to self-renew. The lineage tracing in this study showed ability of these diploid Axin2 cells to replace all hepatocytes all the way to periportal hepatocytes over one year. They also demonstrate that like glutamine synthetase, Axin2 also responds to wnt signaling in an autocrine manner; that wnt signal originated from the hepatic vein endothelial cells, and that hepatocytes renewed by these Axin2 cells lost Axin2 expression as they migrated away from the hepatic vein vicinity towards hepatocytes, in the manner that they lost glutamine synthetase. The renewed hepatocytes take up carbamoyl-phosphate synthase 1, which replace GS and Axin2. Lastly the authors proved that Axin2 truly self-renewed and not preplaced by new Axin2 cells by using other cell labelling methods; i.e. “..while Axin2+ cells can give rise to all the hepatocytes along the lobule, they are not replaced by unlabeled Axin2− cells”. Other findings include Tbx3 gene dependence of Axin2 cells renewability. This study clearly revolutionizes traditional thinking about liver regeneration.

Prepared by:
Rish Pai, MD, PhD; Mayo Clinic Arizona
Sanjay Kakar, MD; University of California, San Francisco
Cindy Guy, MD; Duke University
Wenqing Cao, MD; University of Rochester
Jingmei Lin, MD, PhD; Indiana University
Oyedele Adeyi, MD; University of Toronto
Charles Lassman, MD; University of California, Los Angeles

Journals Reviewed
American Journal of Surgical Pathology, Modern Pathology, Histopathology, Human Pathology, American Journal of Clinical Pathology, Journal of Pathology, Archives of Pathology and Laboratory Medicine, Advances in Anatomic Pathology, Hepatology, Journal of Hepatology, Liver Transplantation, Gastroenterology, Gut, Clinical Gastroenterology and Hepatology, Journal of Gastroenterology and Hepatology, American Journal of Gastroenterology, Nature

Tuesday, July 21, 2015

Journal Watch May-June 2015

American Journal of Surgical Pathology, June 2015


Hyaline Droplets in Kupffer Cells: A Novel Diagnostic Clue for Autoimmune Hepatitis.  
Tucker SM, et al.  Am J Surg Pathol. 2015 Jun;39(6):772-8.

The authors of this study compare autoimmune hepatitis liver biopsies from 30 children to those with hepatitis B and hepatitis C in order to identify any characteristic histologic features of pediatric autoimmune hepatitis.  In half of the pediatric autoimmune hepatitis cases, hyaline droplets were identified in Kupffer cells.  Hyaline droplets were associated with markedly elevated serum IgG levels, and immunohistochemical analysis demonstrated that the globules were positive for IgG, occasionally for IgA, and rarely for IgD.  None of the biopsies from pediatric patients with hepatitis C contained hyaline droplets.  Only one patient with hepatitis B contained hyaline droplets.  The hyaline droplets were readily identified on a PAS/D stain.  The well circumscribed globular and waxy appearance of the hyaline droplets separates it from other material often seen within Kupffer cells.  The authors suggest that hyaline droplets within Kupffer cells can be helpful in the diagnosis of autoimmune hepatitis.  

Am J Pathology, June 2015


Profiles of Cancer Stem Cells Subpopulations in Cholangiocarcinomas. 
Cardinale V et al. Am J Pathol 2015 Jun;185(6):1724-1739

Cancer stem cells (CSCs) from human cholangiocarcinoma (CCA) subtypes (mucin-secreting intrahepatic and perihilar versus a peripheral mixed subtype) where characterized for immunohistochemical markers and tumorogenic potential (subcutaneous injection versus injection into normal and cirrhotic murine livers). The authors found that human CCAs were rich in CSCs and that CSC subpopulations generate different types of cancers depending on the microenvironment.

Histopathology, Apr-Aug 2015


Loss of CD155 expression predicts poor prognosis in hepatocellular carcinoma.
Qu, P, et al.  Histopathology. 2015 Apr;66(5):706-14.

Abnormal nuclear expression of Pygopus-2 in human primary hepatocellular carcinoma correlates with a poor prognosis.

Zhang, S, et al.  Histopathology. 2015 Aug;67(2):176-84.

Low expression of B-cell associated 31 protein in human primary hepatocellular carcinoma correlates with a poor prognosis

Tan, N., et al.  Histopathology. 2015 May 15.

Three papers published recently in Histopathology found three separate markers that correlated with various adverse outcome indices of hepatocellular carcinoma. These are loss of CD155, an immune modulator (Histopathology. 2015 Apr;66(5):706-14); abnormal nuclear expression of Pygopus-2, a co-activator of the Wnt/b-catenin transcriptional and an enhancer of b-catenin function (Histopathology. 2015 Aug;67(2):176-84.); and low expression of BAP31, a B-cell receptor associated protein which when depleted with EpCAM, decreased cyclins D1 and E expression causing suppression PI3K/Akt signaling (Histopathology. 2015 May 15. Epub ahead of print]). The three studies found these three markers to be independently predictive of tumor biology and/or outcome.  Concerning CD155, Qu P. et al found that loss of CD155 expression by immunohistochemistry was associated significantly with “higher serum alpha-fetoprotein level (P = 0.016) and a higher incidence of portal vein tumour thrombus (P = 0.050)”. Also patients with retained expression of CD155 had “better overall survival after surgery than those with negative CD155 expression (P = 0.005)”.

Concerning Pygopus-2, Zhang S et al. reported that abnormal nuclear Pygopus-2 “… expression in HCC patients was associated with age (P = 0.025), tumour size (P = 0.005), intra- or extra-hepatic metastasis (P = 0.029), vascular invasion (P = 0.026) and tumour differentiation (P = 0.004)”, while patients with normal expression had better short term (1-year) and long term survival. A third marker, the B-cell receptor associated protein BAP31, operates at the level of endoplasmic reticulum (ER). The authors based their premises on recent report that ER stress was related to the hepatocellular carcinogenesis and development. Since BAP31 with EpCAM depletion had been reported to reduce cyclins D1 and E causing growth advantage the authors decided to investigate the role of BAP31. Using relative intensity of expression (rather than a positive-negative algorithm), the authors found that “decreased” expression of BAP31 correlated with poor overall survival.

It is difficult to say at these early stages how much a role, if any these prognostic markers will play in clinical management of hepatocellular carcinoma, but just like CK19 before them, they require continuing monitoring as confirmatory (or refuting) evidence unfolds.

Modern Pathology, June 2015 


DNAJB1-PRKACA is specific for fibrolamellar carcinoma 
Graham RP, et al. Mod Pathol. 2015 Jun;28(6):822-9.

In this study, RT-PCR and FISH assays to detect the rearrangements of PRKACA locus were performed on a total of 106 primary liver tumors to test the diagnostic specificity for fibrolamerllar hepatocellular carcinoma. RT-PCR was successful in 92% of tested fibrolamellar carcinoma cases (24/26) and the DNAJB1-PRKACA fusion transcript was not detected in other tumor types, including conventional hepatocellular carcinoma, cholangiocarcinoma, hepatic adenoma, and hepatoblastoma. In addition, FISH and RNA in situ hybridization displayed similar results. In summary, detection of DNAJB1-PRKACA fusion is sensitive and specific to support the diagnosis of fibrolamellar carcinoma.

Liver Transplantation, June 2015


Donation after Cardiac Death Liver Transplantation: Graft Quality Evaluation Based on Pretransplant Liver Biopsy.  
Xia W, et al.  Liver Transplantation.  2015 Jun;21(6):838-46.

Donation after cardiac death has been associated with inferior patient and graft survival.  Thus, many DCD livers are discarded due to concerns of inferiority.  In this study the authors assess the ability of liver biopsy to predict graft survival in 127 DCD liver transplants in China.  The biopsies were assessed for macrovesicular steatosis, hepatocyte swelling, hepatocyte vacuolation, hepatocyte necrosis, and sinusoidal neutrophilic infiltrate.  Factors associated with poor graft survival were macrovesicular steatosis greater than 20% [hazard ratio 2.9] and a sinusoidal neutrophilic infiltrate (> 2 sinusoidal neutrophils per high power field in the most affected area) [hazard ratio 6.9].  The donor characteristic that was associated with poor survival was a high total bilirubin.

Gut, May 2015


Pathobiology of Liver Fibrosis: A Translational Success Story.  
Ye YA, et al. Gut. 64(5):830-41.

In this review, Lee and colleagues discuss the recent developments in hepatic fibrosis with a particular focus on reversibility.  They discuss the cellular sources of fibrosis, the mechanism extracellular matrix deposition, and the pathways that lead to a fibrosis regression.  Antifibrotic therapies are also discussed.  This article may be of interest to those more interested in understanding the mechanisms of fibrosis and novel therapies aimed at reducing hepatic fibrosis.

Journal of Hepatology, June 2015


Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease.
Reilly NR et al. Journal of Hepatology 2015; 62: 1405-1411.

The association of celiac disease (CD) and non-alcoholic fatty liver disease (NAFLD) is unclear. This large population-based cohort study of 16,816 CD patients and 130,051 matched reference individuals with 10 years median follow-up reveals that individuals with CD have significantly higher risk of NAFLD compared to general population. Furthermore, their data indicates the risk of NAFLD is highest in children and is highly increased in the first year after the diagnosis of CD. The risk of NAFLD may persist over a long time (15 years).

Gastroenterology, June 2015


Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. 
Chalasani N, et al.  Gastroenterology. 2015; 148(7):1340-1352.

This is an initial report from 1257 patients enrolled in a prospective study being done by Drug-Induced Liver Injury Network. DILI resulted in chronic liver disease in 17% of cases. Disease severity and mortality tended to be higher in patients with pre-existing disease.  Antimicrobial agents were the most common etiology for cases with a short latent period (≤7  days), while nitrofurantoin and minocycline were most commonly associated with long latency (>365 days). Cholestatic injury was more common in older individuals (>65 years)

β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis.
Monga SP. Gastroenterology. 2015; 148(7):1294-1310.

β-catenin activation has been implicated in hepatocellular neoplasms including adenoma and carcinoma either through mutations/deletions in β-catenin or involvement of other members of the WNT signaling pathway. β-catenin interacts with a variety of transcription factors including T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α, and can regulate the expression of many target genes. This extensive review discusses the role of β-catenin in metabolic zonation, and hepatocellular tumors.

Hepatology, May 2015


Hepatocyte Buds Derived from Progenitor Cells Repopulate Regions of Parenchymal Extinction in Human Cirrhosis

Stueck AE, Wanless IR. Hepatology 2015 May;61:1696-1707

The authors use immunohistochemistry for EpCAM, K19, CD34, glutamine synthetase and Ki-67 to investigate the origin of cells which repopulate the liver following parenchymal extinction lesions. Semiquantitative analysis of the morphologic sequence of hepatic “bud” maturation is described. The authors conclude that the stem/progenitor pathway is manifested by the bud sequence and that the majority of distal cholangiocytes have stem-like properties and the availability of bile ducts/or venous drainage are limiting facts for regeneration.

Hepatology, June 2015


Adaptive Remodeling of the Biliary Architecture Underlies Liver Homeostasis
Kaneko K, et al. Hepatology 2015 June;61:2056-2066.

The authors developed a novel imaging technique using infusion of ink containing carbon black into mice livers following various types of injury in order to visualize the global and fine-scale architecture of the regenerating biliary tree. They show the emergence and expansion of liver progenitor cells along with the structural transformation of the intrahepatic biliary tree. They conclude that the hepatobiliary system possesses structural flexibility and can remodel dynamically and adapt to various injury conditions.

Prepared by:
Rish Pai, MD, PhD; Mayo Clinic Arizona
Sanjay Kakar, MD; University of California, San Francisco
Cindy Guy, MD; Duke University
Wenqing Cao, MD; University of Rochester
Jingmei Lin, MD, PhD; Indiana University
Oyedele Adeyi, MD; University of Toronto
Charles Lassman, MD; University of California, Los Angeles

Journals Reviewed
American Journal of Surgical Pathology, Modern Pathology, Histopathology, Human Pathology, American Journal of Clinical Pathology, Journal of Pathology, Archives of Pathology and Laboratory Medicine, Advances in Anatomic Pathology, Hepatology, Journal of Hepatology, Liver Transplantation, Gastroenterology, Gut, Clinical Gastroenterology and Hepatology, Journal of Gastroenterology and Hepatology, American Journal of Gastroenterology