Friday, March 27, 2015

Congratulations to Winners of 2015 HPHS Trainee Award!

Winner of The 2015 HPHS Best Abstract
Dr. Emily Waterhouse & Dr. David Solomon (UCSF,  faculty sponsor. Linda Ferrell):
Validation of an RT-PCR assay for detection of recurrent DNAJB1-PRKACA fusion transcripts in fibrolamellar hepatocellular carcinoma

Drs. Fiel, Waterhouse, Solomon and Adeyi


First Runner-up Abstract
Dr.  Christos Tsokos,  UCSF (faculty sponsor Gregor Krings):
Telomerase Reverse Transcriptase Promoter Mutations (mTERTp) in Combined Hepatocellular(HCC)-Cholangiocarcinoma(CC; cHCC-CC) Support Clonal and HCC-like Origin for Both Components

Drs. Fiel, Tsokos and Adeyi


Second Runner-up Abstract
Dr. Dana Balitzer,  UCSF (Faculty sponsor -  Sanjay Kakar):
Autoimmune Hepatitis: Review of Validity of Histologic Features Included in the Simplified Criteria Proposed by the International Autoimmune Hepatitis Group (IAIHG)

Drs. Fiel, Balitzer and Adeyi

Monday, March 23, 2015

Hans Popper Hepatopathology Society Companion Meeting 2015 Handouts

Hans Popper Hepatopathology Society
Sunday, March 22, 2015 - 8:30am to 12:00pm
Hynes Convention Center Ballroom B
8:30 AMCompanion Meeting Moderator- M. Isabel Fiel, MD, Mount Sinai Medical Center, New York, NY Maria Isabel Fiel, MD
8:30 AMLiver Pathology and the Clinician in 2015: At the Crossroads Thomas D. Schiano, MD
8:30 AMPractical Issues and Diagnostic Challenges in Liver Pathology Maria Isabel Fiel, MD
8:50 AMDifferential Diagnosis of Fatty Liver Disease: Not the Usual Culprits Elizabeth M. Brunt, MD
9:20 AMNoncirrhotic Portal Hypertension and Pathology of the Sinusoids Ian R. Wanless, MD
9:50 AMQuestion and Answer Session Maria Isabel Fiel, MD
10:00 AMCoffee Break Maria Isabel Fiel, MD
10:30 AMUpdate on Cholangiocarcinoma and Mixed Hepatocellular-Cholangiocarcinoma Emma E. Furth, MD
11:00 AMBiomedical Informatics 101 Arief Suriawinata, MD
11:20 AMSpecial stains, Immunohistochemistry and Genomic Testing of the Liver: A Guide for the Practicing Pathologist Michael S. Torbenson, MD
11:50 AMQuestions and Answers Maria Isabel Fiel, MD

Tuesday, March 10, 2015

President's Message March 2015

Dear Friends and Colleagues,

I would like to remind you that the HPHS Companion Society Meeting at Boston is scheduled for March 22, 2015 from 8:30am-12 noon. The title is “Diagnostic Challenges and Update in Hepatopathology”. We have created a program that will not only be very educational to our members but will hopefully be interesting to non-members as well. The topics that will be discussed include new therapeutic interventions for hepatitis and liver cancer and what this means to the pathologist, differential diagnosis of fatty liver diseases, vascular diseases and portal hypertension, the basics of biomedical informatics and its applicability in general practice, diagnosis of mixed hepatocellular-cholangiocarcinoma, and the current methods available to assist in reaching a diagnosis in challenging liver pathology cases. 

The Business meeting will immediately follow the companion meeting. Members are encouraged to attend, as we will need to vote on some modifications to the bylaws as a result of the tax-exempt status of the HPHS, as well as some changes to the duties and responsibilities of the members of the Executive Committee.

Please encourage both your junior and senior colleagues to officially become members of the HPHS. Residents and fellows can become Trainee members without having to pay any dues. They can easily transition to Regular membership once they finish their training. Application to membership is available on the website. Please email completed application to Maha Guindi (Maha.Guindi@cshs.org), chair of the membership committee.

I look forward to seeing you all in Boston.

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

Monday, March 9, 2015

Interesting Case March 2015

Clinical History
A 30 year old man was referred for liver transplantation workup for presumed liver cirrhosis from NASH. The clinical diagnosis of NASH cirrhosis was based on hepatosplenomegaly, low platelets and steatosis on liver imaging and the local biopsy. The only risk factor for NASH was hypercholesterolemia. 

Labs
AST 53 U/L, ALT 87 U/L, ALP 75 U/L, platelets 101,000/µL.

The patient was referred to a liver transplantation center and the biopsy was re-evaluated. Images from the liver biopsy are shown below.



Liver Biopsy Findings
The biopsy shows clusters of “sea-blue” cells that contain pale, foamy cytoplasmic material. These cells stain with the macrophage marker CD68, but not the hepatocyte marker Hep-Par1. The hepatocytes have mild microvesicular steatosis, but no features of steatohepatitis are apparent. Also there is only very little fibrosis. By electron micrograph, the macrophages contain laminated myelin figures.

Diagnosis
Sea blue histocytosis syndrome

Major Learning Points
  1. Clinical, non-invasive features of cirrhosis and portal hypertension, such as thrombocytopenia, can have other causes.
  2. Sea-blue histiocytosis (SBH) syndrome can be subtle and not always as prominent as in this case. But SBH syndrome should be kept in mind in certain clinical contexts, including unexplained hepatosplenomegaly.
  3. The published cases of SBH involving the liver are for the most part due to inherited lysosomal storage disorders. Typically the bone marrow is the most commonly affected organ, baring a few exceptions such as patients receiving fat emulsion in total parenteral nutrition.
  4. Electron microscopy, though rarely utilized in today’s clinical hepatopathology practice, could play a helpful role in defining the nature of cytoplasmic accumulations.
Discussion
Steatohepatitis is a common disease and it has become a frequent cause of referral to liver transplantation centers. In addition, the proportion of liver transplantations for NASH is projected to increase due the availability of new highly efficacious direct antiviral agents for hepatitis C. It is worth highlighting the need to carefully evaluate the clinical, non-invasive parameters of cirrhosis knowing that these assessments are surrogates and can sometimes produce false positive results. In this patient with an enlarged spleen, low platelets, hyperlipidemia and radiologic diagnosis of “fatty liver”, the clinical assessment had pointed in the direction of NASH-related end-stage liver disease. Ultimately, however, this proved to be a case of Nieman-Pick disease which manifests characteristically as hepatosplenomegaly, low platelets and hypercholesterolemia.

The accumulation of lipid material in macrophages of several organs, including the liver, spleen, bone marrow, and lymph nodes, is sometimes referred to as “sea-blue histocytosis” (SBH). The name initially originated form the appearance of these macrophages when stained with Giemsa/PAS, although in the case described above this stain was not necessary to demonstrate these cells. There are many causes of SBH, but in general, it is a feature of lipid or ceroid storage disorders, and can be primary or secondary. The term was first applied in 1941 in the Swiss literature by Dr.  Möschlin and later reported as a syndrome in 1970 by Silverstein et al (N Engl J Med 1970; 282:1-4). The syndrome was attributed to adults with Nieman-Pick disease (NPD) in 1977 by Long et al (Am J Med. 1977;62(4):627-35). NPD was ultimately diagnosed in the patient presented above. Following additional studies, he is believed to have Nieman-Pick disease type B. The SBH syndrome is however not unique to NPD and histopathology lacks the specificity to make an etiologic diagnosis in most cases. 

Determining an etiology for SBH syndrome requires the combination of clinical, histopathological, biochemical and genetic information. Some of the other primary/inherited diseases associated with the SBH are cholesterol ester storage disease, Gaucher disease, hypertriglyceridemia (with mutation in the receptor-binding region of the apoE molecule), lecithin-cholesterol acyltransferase deficiency (i.e., Norum disease), ceroid lipofuscinosis and Tangier disease. Several acquired conditions have also been associated SBH, including administration of fat emulsion in total parenteral nutrition, as well as some hematologic conditions. The bone marrow, and less likely the liver, is the usual site of SBH accumulation in these hematologic conditions, such as in myelodysplastic syndrome (J Clin Pathol. 1993 Nov;46(11):1030-2).

Contributed by:
Oyedele Adeyi, MD
Department of Pathology, Toronto General Hospital, Toronto, Ontario.

Monday, February 2, 2015

In Memoriam Boris Henry Ruebner, MD, 1923-2014

Boris H. Ruebner, MD, 1923-2014
Boris, a long time member of the Hans Popper Hepatopathology Society, passed away June 11, 2014 at the age of 90. Boris was born in Düsseldorf. He recalled to me that, at the age of 13, he attended the 1936 Berlin Olympics with his father. He moved to England in the late 1939 where he attended Winchester College, followed by the University of Edinburgh Medical School. After graduation in 1946, he studied and practiced pathology at Hammersmith Hospital in London and the University of Heidelberg. He emigrated to Canada where he was a member of the pathology staff of Dalhousie University in Halifax from 1957 to 1959. He was married on campus in King’s College Chapel. Together, we visited the same chapel during the 2007 Laennec meeting, shortly before his 50th wedding anniversary.

Boris was on the staff of Johns Hopkins University for a decade before being recruited, in 1968, to the inaugural staff of the University of California (Davis). During his long career, he published more than 180 peer-reviewed articles. He was well known for his textbook “Pathology of the Liver and Biliary Tract”, co-authored with Carolyn Montgomery (1982 and 1991). Although Boris officially retired in 1994, he maintained a consultation practice and continued to teach into his late 80s. He was a popular and award-winning teacher. In recognition of his contribution, the Division of Gastroenterology created the Ruebner-Rosenquist Outstanding Teaching Award in 2010.

I was first acquainted with Boris through his writings. While pursuing a project at Johns Hopkins in the 1980s, I reviewed all the autopsy liver slides on file from a period of 80 years and assembled some data. Afterwards, I discovered that Boris had reviewed the same liver slides and had already published similar data.  Boris was always a step ahead of me! We finally met in person at the inaugural planning for the Hans Popper Hepatopathology Society during a USCAP meeting. A few years later, he became one of the founding members of the Laennec Liver Pathology Society. He was present at the first summer meeting in 2000 and every subsequent annual meeting until he was 88. He was a committed traveller and made the Laennec meetings a reason to get about, scrambling over rocks and roots with the fittest. He suffered a ruptured tendon in his mid-80s but continued to press on with the help of great personal tenacity and a stout cane. One memorable summer, at the age of 84, he visited the Hermitage in St Petersburg and returned, travelling alone, with a stop in Nova Scotia to attend the Laennec meeting. From there he took a bus to New York where he boarded his return flight to Davis. He still had the strength to attend 4 annual meetings after that. Travel was a tonic for him, just as his determination was a tonic for us. He was always with us, and now we miss him.

Ian R. Wanless, M. D.
Department of Pathology,
Dalhousie University, Halifax, Canada

Monday, December 15, 2014

President's Message December 2014

Dear Friends and Colleagues,

I would like to remind you that the HPHS  Companion Society Meeting at Boston is scheduled for March 22, 2015 from 8:30am-12 noon. The title is “Diagnostic Challenges and Update in Hepatopathology”. We have created a program that will not only be very educational to our members but will hopefully be interesting to non-members as well. The topics that will be discussed include new therapeutic interventions for hepatitis and liver cancer and what this means to the pathologist, differential diagnosis of fatty liver diseases, vascular diseases and portal hypertension, the basics of biomedical informatics and its applicability in general practice, diagnosis of mixed hepatocellular-cholangiocarcinoma, and the current methods available to assist in reaching a diagnosis in challenging liver pathology cases. Please see the last page of this Newsletter for the list of speakers and the title of their talks. 

The Business meeting will immediately follow the companion meeting. Members are encouraged to attend, as we will need to vote on some modifications to the bylaws as a result of the tax-exempt status of the HPHS, as well as some changes to the duties and responsibilities of the members of the Executive Committee. Please encourage both your junior and senior colleagues to officially become members of the HPHS. Residents and fellows can become Trainee members without having to pay any dues. They can easily transition to Regular membership once they finish their training. Application to membership is available on the website. Please email completed application to Maha Guindi (Maha.Guindi@cshs.org), chair of the membership committee. 

We have officially created a new Website Committee, and I am grateful that Dr. Arief Suriawinata has graciously agreed to be the Chair of this committee. Please see the website for new updates including the discussion and main learning points for the two interesting cases presented in this Newsletter. I would also like to thank Dr. Bita Naini, past member and the new Chair of the Newsletter Committee as the person behind the scenes in making this Newsletter go out. 

I look forward to seeing you all in Boston.

Sincerely,

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

Friday, December 12, 2014

Interesting Case December 2014 #1

Clinical History:

A 29 year old woman with a 5 year history of insulin dependent diabetes mellitus presented with right flank pain and constipation for the past 2 weeks. During the clinical work up, she was diagnosed with diabetic ketoacidosis and acalculous cholecystitis. Due to elevated liver enzymes and hepatomegaly, liver biopsy was performed during the laparoscopic cholecystectomy.

Labs:

At the time of presentation, the patient’s laboratory values were: blood glucose, 434 mg/dL (normal range [NR] 70-100 mg/dL); alkaline phosphatase, 131 U/L (NR 14-127 U/L); AST, 457 U/L (NR 5-46 U/L); ALT, 230 U/L (NR 4-51 U/L) and total bilirubin, 1.1 mg/dL (NR 0.1-1.5 U/L). 

Microscopic Images:


Figure 1. Low power view showing pale liver parenchyma without steatosis or inflammation.

Figure 2. Swollen and rarified hepatocytes with compressed sinusoids.

Figure 3. Hepatocytes with multiple giant mitochondria and glycogenated nuclei.

Diagnosis

Glycogenic Hepatopathy

Discussion

Glycogenic hepatopathy (GH) is not currently commonly seen in practice due to improved diabetic therapies. The typical clinical presentation is elevated blood glucose, elevated liver enzymes, hepatomegaly and abdominal pain. Other signs and symptoms can include abdominal distension, anorexia, nausea, right upper quadrant pain and shortness of breath. The liver biopsy in GH characteristically shows marked accumulation of glycogen in hepatocytes, but the diagnosis requires close clinicopathological correlation. 

The pathophysiology of GH is incompletely understood, but it is thought to be caused by prolonged periods of hyperglycemia in poorly controlled diabetic patients treated with insulin. The elevated blood glucose passes into hepatocytes independent of insulin. This is then followed by periods of insulin therapy in which the hepatic glucose is converted to glycogen and the glycogen becomes trapped in hepatocytes. It is thought that the excess hepatic glycogen accumulation leads to hepatocyte injury and causes “leakage” of aminotransferases. Significant hepatocellular death is not typical.

GH also been reported in patients with type II diabetes mellitus, urea cycle defects, and medication effects (e.g., short-term high dose steroids). The differential diagnosis includes hereditary glycogen storage diseases, smooth endoplasmic reticulum proliferation due to medication effects, and glycogen pseudoground glass changes associated with the intake of multiple medications (poly- pharmacotherapy). Rarely GH can coexist with NAFLD or steatohepatitis. Minimal fibrosis has rarely been described in GH; significant fibrosis is not characteristic.

Case contributed by

Jie Ouyang, M.D. 
Florida Hospital Center for Diagnostic Pathology 
Orlando, Florida 

References



Interesting Case December 2014 #2

Clinical history

This biopsy is from a 62 year old male who underwent liver transplantation 6 months prior for decompensated hepatitis C cirrhosis and multifocal hepatocellular carcinoma. Two months prior to this biopsy (4 months post-transplant) the patient’s laboratory studies were abnormal with ALT 57, AST 69, ALP 149, total bilirubin 17.3 mg/dL (296 umol/L) and the liver biopsy at that time showed features consistent with fibrosing cholestatic recurrent hepatitis C. The patient was urgently treated with Simeprevir and Sofosbuvir, in addition to his other medications which included prednisone and Tacrolimus. At the time of this biopsy, two months after commencing HCV treatment, his viral RNA was down to 1 log but his liver enzymes began to rise with mainly a cholestatic pattern with ALT 13 U/L, AST 26 U/L, ALP 1032 U/L, total bilirubin 2.7 mg/dL (46 umol/L). Imaging showed no evidence of bile duct dilatation, however, he was deemed too ill for MRCP or ERCP. A liver biopsy was obtained; representative pictures are shown below.

Microscopic images

Figure 1

Figure 2

Figure 3A
Figure 3B

Figure 4
The liver shows mild portal and scanty lobular inflammation (Figure 1-3). The portal tracts, however, are expanded by mild edema, a mild ductular reaction, and the inflammation includes neutrophils. Overall these findings simulate those of biliary obstruction. Fibrosis is mild in the subsinusoidal and periportal areas, but not progressed significantly compared to the biopsy obtained two months earlier. Additionally there is less severe hepatocellular injury compared to the prior biopsy. No viral inclusions are apparent, but occasional foci of neutrophilic microabscesses are identified. The patient was known to have been CMV mismatched with his donor (recipient negative anti-CMV Ab; donor positive). CMV immunohistochemistry was obtained and many cells were positive, most of which were neither “megalic” nor apparent on routine stains, even in hindsight (Figure 4).

Diagnosis

Post-transplant CMV syndrome presenting biochemically and histopathologically as biliary obstruction.

Main Learning Points:


  • A combination of immunosuppression, a “sick” patient and unfavorable serology (e.g., CMV recipient-donor mismatch) should always prompt a search for CMV.
  • Histopathologically, “classical” CMV inclusions have low sensitivity and are typically rare even in the most severe cases. 
  • Diagnosis of CMV infection post-transplant therefore depends more on clinical suspicion rather than initial identification of possible viral inclusions.
  • In the liver, biliary epithelia are known targets of CMV either directly or indirectly via injury to peribiliary plexus endothelial cells.
  • Biliary strictures from mechanical causes are more common than CMV-induced biliary injury, but one should consider CMV infection in the differential diagnosis especially in a suggestive clinical context as described above.

Discussion

With the use of prophylactic and pre-emptive antiviral therapy, cytomegalovirus symptomatic infection now occurs in only about 2-10% of transplanted patients. It usually occurs in the first few months after transplantation and the most important risk factor for the development of the disease is the combination of a seropositive donor with a seronegative recipient. In solid organs transplantation, the graft is particularly prone to infection.

The characteristic and most common histological finding in CMV hepatitis, in our experience, is the presence of neutrophilic aggregates/microabscesses or satellitosis within the parenchyma. Viral inclusions can be seen in hepatocytes, endothelial cells and biliary epithelial cells, but they are often sparse. When suspected, the use of deeper levels and immunohistochemistry should be performed.  

CMV infection has been associated with an increased risk for other allograft complications such as chronic rejection and biliary compromise. Biliary complications due to CMV have been reported to occur at a mean post-transplant period of 8.4 months (Liver Transplantation. 2013;19(10):1142-1150), and in this series CMV was detected in the tissues of some patients with undetectable virus in the peripheral blood by PCR. Biliary strictures could also result in part from damage to endothelium of small size hepatic arteries and/or peribiliary plexus. 

The histological alterations associated with hepatic CMV infection may cause differential diagnostic problems as inclusions are rarely found. Other infections (bacterial, fungal and viral) or non-infectious conditions (graft ischemia and biliary obstruction) can be associated with neutrophilic microabscesses.  Nevertheless a high index of clinical suspicion and occasional neutrophilic microabscesses (arrows in figure 3) in the appropriate clinical setting should prompt immunohistochemistry for the virus. In our practice we tend to order CMV immunohistochemistry on most liver biopsies performed for cause in the first 6 months post-transplant (including liver, bone marrow or other solid organ transplant) irrespective of the clinical presentation. It is also worth noting that inflammation is typically sparse in CMV “hepatitis”. Indeed, abundant inflammation may be indicative of CMV occurring together with some other condition.

In this patient, response to HCV treatment was characterized by improved bilirubin, drop in viral RNA load, and less prominent hepatocellular swelling/disarray. However, CMV PCR in the peripheral blood soon after the second biopsy showed a titer of 4 logs and the CMV titer had been undetectable prior to HCV treatment 2 months earlier. The preceding biopsy had been negative when stained for CMV. The question therefore is: do these new antiviral agents come with increased risk for CMV infection specifically and/or for opportunistic infections in general? The answer is not known but as we gain increasing experience with these drugs, new issues will certainly emerge for the pathologist to consider, and CMV reactivation may be one to keep an eye on. Also the question of a biliary stricture not related to CMV (e.g., anastomotic) cannot be ruled out on the basis of histopathology alone, even with a positive CMV, and the possibility further exploring other causes biliary stricture should be raised.

Case contributed by

Aude Roussel-Jobin, M.D. Fellow, Liver Pathology University of Toronto

References:

Hübscher SG, and Clouston AD, Transplantation pathology. In: Burt A, Portmann L, and Ferrell L, MacSween’s Pathology of the Liver. 6th edition. Churchill Livingstone Elsevier, 2012: 877-878.

Adeyi O, Fischer S and Guindi M. Liver allograft pathology: approach to interpretation of needle biopsies with clinicopathological correlation. J Clin Pathol 2010; 63:47-74.

Gotthardt DN1, Senft J, Sauer P, Weiss KH, et al. Occult cytomegalovirus cholangitis as a potential cause of cholestatic complications after orthotopic liver transplantation? A study of cytomegalovirus DNA in bile. Liver Transpl. 2013;19(10):1142-1150.

Adeyi O. Liver Transplant Pathology. In: Ferrell LD, Kakar S, editors. Consultant Pathology: Liver Pathology. 1st ed. New York City: Demos Medical, 2011:307-342.

Wednesday, September 3, 2014

Annual Membership Dues via PayPal is now LIVE!

Dear Hans Popper Hepatopathology Society Members,

We are happy to inform everyone that you may now contribute your annual membership dues via PayPal within the HPHS website.

As you know, we will continue to have dedicated speakers each year, which, of course, requires ongoing funding. We appreciate your attention to our dues notice.

Once again, thank you for your exceptional support of the HPHS.

Grace E. Kim, MD
Secretary –Treasurer,
Hans Popper Hepatopathology Society

Tuesday, August 26, 2014

President's Message August 2014

Dear Friends and Colleagues,

I am delighted to inform you that, thanks to Grace Kim’s hard work and dedication, the Hans Popper Hepatopathology Society is now officially a Non-Profit Organization and has garnered 501(3)(c) tax-exempt status officially recognized by the IRS. Additionally, the HPHS bank account has been set up locally in California. Further details from Grace are found in this newsletter.

The HPHS Companion Society Meeting is scheduled for March 22, 2015 from 8:30am-12noon. The title is “Diagnostic Challenges and Update in Hepatopathology”. We have created a program that will not only be very educational to our members but will hopefully be interesting to non-members as well.

The Business meeting will immediately follow the companion meeting. Members are encouraged to attend as we will need to vote on some modifications to the bylaws as a result of the tax-exempt status of the HPHS, as well as some changes to the duties and responsibilities of the members of the Executive Committee, and finally to officially create a Website Committee. In the meantime, I would like members to volunteer to serve on this committee. Please email me directly (mariaisabel.fiel@mountsinai.org) if you are interested.  In the near future, we will have the ability to check off on-line our interest in committee membership when we pay our yearly dues. Currently, Arief Suriawinata is overseeing the website with the help of Vince Hoang, Grace Kim’s Administrative Assistant. Vince has replaced Julie Gutierrez, who was an invaluable help to Beth Brunt with the membership dues, correspondence, and all other HPHS matters for many years. We thank Julie for all of her efforts throughout the years!

The Call for Abstracts for the “Pathologist-in-Training Award” is now official. Deadline for submission to Dele Odeyi (oyedele.adeyi@uhn.ca), Chair of the Education Committee, is March 6, 2015. Please encourage your residents and fellows to submit their work to the HPHS.

Finally, please encourage both your junior and senior colleagues to officially become members of the HPHS. Residents and fellows can become Trainee members without having to pay any dues. They can easily transition to Regular membership once they finish their training. Application to membership is available on the website. Please email completed application to Maha Guindi (Maha.Guindi@cshs.org), chair of the membership committee.

I hope everyone is having a great summer. I look forward to seeing you in Boston.

M. Isabel Fiel
President,
Hans Popper Hepatopathology Society