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“The Long Journey of
Hepatology from the 1960s to
our Days”
Stephanos J. Hadziyannis, M.D.
Emeritus Professor of Medicine
Athens University, School of Medicine
The roots of Hepatology appear to be very deep
going back to the Ancient Years of Hippocratic
and Galenic Medicine. The liver and spleen
were considered responsible for the production
of 2 of the 4 humors of our body: the yellow
and black bile and the black bile was thought to
be responsible for the development of
depression (Μέλαινα Χολή= Melancholy)
However, the evolution of Hepatology over the
Centuries was slow and with little knowledge
on liver structure and function in health and
disease, as stressed by Georg Budd in 1853 in
his book Diseases of the Liver
Then, after the 19th Century several
important developments and
breakthrough discoveries took place in
research and clinical practice of Liver
Diseases
These culminated in the 1950s and
1960s, to the development and subsequent
flourishing of Hepatology as an
independent Clinical and Scientific
Discipline
In this Presentation:
I will focus on the Journey of Hepatology that I have
witnessed during the last 50 years, the journey that
started in the 1960s with the landmark discovery of the
Hepatitis B Virus and reached in our days to the cure of
chronic hepatitis C by DAAs
Of course the long journey has not ended it continues full
speed and a lot of imagination is needed if one tries to
guess what the scenery of Hepatology will be, even in
the few next years
• The journey of Hepatology of the last 50
years covers at least 10 condensed chapters
of Liver Diseases including their diagnosis,
prevention, pathogenesis, natural course,
medical/surgical treatment and liver
transplantation
Areas and Directions of the Journey of
Hepatology of the Last 50 Years
• 1. Hepatitis B including hepatitis Delta
• 2. Hepatitis C
• 3. Hepatitis A and Hepatitis E
• 4. Autoimmune Liver Disease
• 5. Cholestatic Liver Disease
• 6. Hepatocellular Carcinoma
• 7. Hereditary and Metabolic Liver Diseases
• 8. Alcoholic Liver Disease including Steatohepatitis
• 9. Non-Alcoholic Fatty Liver Disease (NAFLD)
• 10. Drug-induced liver Injury
I will start with the identification in 1965, by
B.S.Blumberg, a scientist who was looking around the
world for genetic polymorphisms of lipoproteins, of a new
protein initially referred as Australia Antigen
• In a couple of years (1967) this antigen
(A) proved to be a serendipity discovery
of the envelope protein of the HBV itself
(B) and soon thereafter (1969 and 1970)
it was revealed that this virus caused not
only acute but also chronic infection; and
that the last was a major public health
problem worldwide of chronic liver
disease, cirrhosis and hepatocellular
carcinoma (ΗCC)
A
B
But before going on with Viral Hepatitis
a glance at Hepatology during the 1960s
is of order
• “Hepatology” had already started to emerge as a
new clinical and scientific discipline mostly linked
but also independent from Gastroenterology
• Myself after acquiring the specialty of Internal
Medicine in 1962, I became involved in clinical and
experimental studies of Hepatic Enzymology, but I
resisted to join Gastroenterology; and in 1967 I
continued with further research and training in
Hepatology in the Department of Medicine of Dame
Sheila Sherlock in the RFH at Gray’s Inn Road of
London
Dame Sheila Sherlock
(The Liver Queen)
Few Departments of Medicine worldwide
were involved in Hepatology with the
main topics being:
• Alcoholic liver disease
• Drug-induced liver disease
• Haemochromatosis
• Hereditary liver disorders
• Autoimmune Hepatitis
• Primary Biliary Cirrhosis
Dame Sheila at the RFH with staff,
students, fellows and visitors
Hans Popper and Jaque Caroli in the
1970s
Adolph Martini and Saul Krugman
Rudi Smidt and Kunio Okuda
• Dame Sheila together with a number of
American, European, and Asian pioneers
was trying to shape the expanding new
specialty, to draw the portrait of the
clinical hepatologist , to support and
promote the activities of already existing
Liver Societies Association and contribute
to the foundation of new ones :
• The American Association for the Study of
Liver Diseases (ASSLD) founded in 1950
• The International Association for the Study
of the Liver (IASL), founded in 1958
• The European Association for the Study of
the Liver (EASL) founded in 1966 and
dedicated to the pursuit of excellence in
liver research and in the Clinical Practice
of Hepatology (Liver Diseases)
Qualities of the Hepatologist
(as described by J.Caroli in the late 1960s)
Additions to the Previous Portrait of the
Hepatologist
Α.
• “Well Trained and Capable in ”:
• New imaging techniques (CT, MRI, Colored Doppler, PET)
• Interventional techniques and methods, mainly radiologic and endoscopic
• Virology, molecular biology and genetics
• Cellular immunology, cytokines and flow cytometry
Further additions to the previous portrait
« well trained and capable in»:
• Pharmacology, pharmacogentics , antivirals and, immunomodulatory drugs
• All levels of Oncology
• Broad spectrum of the Discipline of Liver Transplantation: From the evaluation of candidate patients to pre- and post-transplantation follow-up and antiviral and anti-rejection treatment
Going back to the long journey of
Viral Hepatitis B from the
discovery of the protein of its
envelope and of its virions to our
days
Milestones in Viral Hepatitis B From the Discovery of the Virus to 2015
1965: Serendipity discovery of Au Ag, the envelope protein of
HBV, subsequently renamed to HBsAg
1970: Screening for HBsAg of blood donors
1981: Development of the first HBV vaccine : A triumph of
preventive medicine an effective vaccine against
acute and chronic HBV liver disease and against
HBV-related hepatocellular carcinoma (HCC)
1990: Approval of IFN-α for the treatment of CHB
1998: Approval of Lamivudine the first anti-HBV NA
2000: Medicare Approval for Liver Transplantation
2002-2014: Approval of Adefovir, Peg-IFNα, Entecavir,
Telbivudine and Tenofovir
Currently: New therapies in the Pipeline of several
Pharmas, under various phases of development
What Can Current Anti-HBV
Therapies Achieve?
They suppress but do not eliminate HBV
They achieve only low rates of HBsAg loss and
only partial reversion of liver necroinflammation
and fibrosis
They decrease but they do not eliminate the
risk for development of HCC
And thus we are looking hopefully forward to future
therapies that may eradicate HBV, reverse completely
liver damage and prevent cirrhosis and HCC
Thus in 2015 Hepatitis B
Is manageable but not curable*
Unfortunately, with a
large diagnostic deficit worldwide
But fortunately, on the other hand, with
an effective vaccine
* ”Functional cure” in case of HBsAg
loss
F
2000 BC
First recorded
references to
hepatitis
epidemics
1963-65
Discovery of Australia
antigen, later called
HAA and finally HBsAg
(Baruch Blumberg and
colleagues)
1947
Differentiation of
hepatitis A from
hepatitis B
(MacCallum, in
human volunteers)
1970
Discovery by electron
microscopy of whole
Hepatitis B Virus
particles
in blood samples (DS
Dane)
1973-1974
Discovery of the
Hepatitis A Virus
(Feinstone,
Hilleman
et al)
1977
Mario Rizzetto et
al discover the
Hepatitis Delta
Virus
1983
Mikhail Balayan
describes the
Hepatitis E Virus
1989
M. Houghton et
al,
discover the
Hepatitis C
Virus
Chronology of The Discovery of the 5
Hepatitis Viruses
1989: Discovery of the Hepatitis C
Virus•
Hepatitis C, previously known only as non-A, non-B hepatitis, was first identified by scientists at the Centers for Disease Control and Prevention (CDC), the NIH and industry (Houghton, Choo, Kuo, Bradley and colleagues). This was a Nobel-worthy achievement both because of its public health impact and for the new methodology formulated to clone the virus
• Its discovery also spurred research into development of therapeutic agents. The genetic diversity of hepatitis C and the relatively weak immune response elicited by the infection posed formidable barriers to vaccine development
Several extrahepatic manifestations
have been described in HCV
• Endocrine
• Hematologic disorders
• Lymphoproliferative disorders/Non-Hodgkin Lymphomas
• Rheumatic disorders • Mixed cryoglobulinaemia
• Dermatologic disorders
• Central nervous system disorders
• Miscellaneous other
1991: The First HCV
Treatment
The FDA of USA approved the first-ever treatment for hepatitis C. This treatment consisted of interferon alpha-2b, but few patients receiving treatment achieved a sustained virologic response. The cure rate was only 6% but increased significantly with the combination with ribavirin.
• (
Development of cell based culture systems that supported HCV,
first using the replicon and then later the infectious JFH1 virus
systems , which enabled high throughput drug screening and the
discovery of obligate cellular HCV receptors
Characterization of HCV protein structures, which greatly
facilitated the design of direct-acting antiviral drugs (DAAs)
2011 Approval of the first generation of antiviral agents
called protease inhibitors (PIs). These agents were found to
act directly on the nonstructural proteins of the hepatitis C virus
to interrupt viral replication and assembly in host hepatocytes.
When they were combined with 24-48 weeks of pegylated
interferon and ribavirin, cure rates among persons infected with
hepatitis C genotype 1 improved to 70%
Milestones and Major Advances in the
Treatment of HCV to 2015
The first generation protease inhibitors of HCV, extended to nucleotide and non-nucleotide inhibitors of NS5B, to inhibitors of NS5A, to second generation protease inhibitors and to several combinations of DAAs
Their development is linked with important scientific, clinical, and regulatory efforts and evolutions that have culminated in their approval for the treatment of Hepatitis C and with cure rates
of 90%-100%
A Reminder on the Clinical Development
of DAAs:
Currently we Stand at the
Beginning of the End of HCV
Thus the current word is cure of
hepatitis C and this is one of the most
significant medical developments of
the last 50 years
(Greg Everson, 2014)
Areas and Directions of the Journey of
Hepatology of the Last 50 Years
• 1. Hepatitis B including hepatitis Delta
• 2. Hepatitis C
• 3. Hepatitis A and Hepatitis E
• 4. Autoimmune Liver Disease
• 5. Cholestatic Liver Disease
• 6. Hepatocellular Carcinoma
• 7. Hereditary and Metabolic Liver Diseases
• 8. Alcoholic Hepatitis and Steatohepatitis
• 9. Non-Alcoholic Fatty Liver Disease (NAFLD)
• 10. Drug-induced liver Injury
Autoimmune Liver Disease in the
1960s
Chronic active hepatitis with ANA and SMA
serology (also referred as Autoimmune and
Lupoid Hepatitis) had already been identified
by Ian Mackay and the AMA of Primary
Biliary Cirrhosis had just been described by
Roitt and Doniach (1966 in Clin & Exp
Immunol)
1967-68 Αt the old RFH
with Peter Scheuer on
liver histopathology and
immunofluorescence
Lupus-like ANA in Autoimmune Hepatitis
Mitochondrial, Parietal-Cell and Thyroid Autoantibodies in PBC
• George Dalekos, who has boarded the boat of
Hepatology several years ago, has contributed, among
else, with ongoing research to the development of the
current state of knowledge on autoimmune liver
disease. This becomes obvious from his recent article of
Jan 2015:
• Nikolaos K Gatselis, Kalliopi Zachou, George K Koukoulis, George
N Dalekos. Autoimmune hepatitis, one disease with many faces:
Etiopathogenetic, clinico-laboratory and histological characteristics.
World J Gastroenterol 2015 January 7; 21(1): 60-83.
• Distinction of AIH in types I and II is based on tissue
immunofluorescence pattern of serum autoantibodies
Autoantibody Profile of Autoimmune Hepatitis Type I
Liver-Kidney Antibodies in Autoimmune Hepatitis Type II
Autoimmune Hepatology also includes numerous
Hepatic and Extrahepatic Syndromes identified
during the last 5 decades
• Dry gland “sicca” syndrome
• Sjögren’s syndrome
• Rheumatoid arthritis
• Autoimmune thyroid disease
• Renal tubular acidosis
• Mixed connective tissue disease (MCTD)
• Polymyositis
• Polymyalgia rheumatica
• Pulmonary fibrosis
• CREST syndrome
• Systemic lupus erythematosus (SLE)
• Pernicious anemia
• Ulcerative colitis
• Exogenous pancreatic insufficiency
• Myasthenia gravis
Areas and Directions of the Journey of
Hepatology of the Last 50 Years
. • 1. Hepatitis B including hepatitis Delta
• 2. Hepatitis C
• 3. Hepatitis A and Hepatitis E
• 4. Autoimmune Liver Disease
• 5. Cholestatic Liver Disease
• 6. Hepatocellular Carcinoma
• 7. Hereditary and Metabolic Liver Diseases
• 8. Alcoholic Hepatitis and Steatohepatitis
• 9. Non-Alcoholic Fatty Liver Disease (NAFLD)
• 10. Drug-induced liver Injury
In all Areas of Hepatology the Journey Continues:
Examples:
“Novel Targets and Therapies in Liver Disease”
• An Emerging Trends Conference
• AASLD and Industry ColloquiumMarch 20-21, 2015 at the Hilton Durham
Research Triangle Park, NC
Comprising small molecule Farnesoid X Receptor (FXR)* agonists for the treatment of liver diseases
including nonalcoholic fatty liver disease also referred as nonalcoholic steatohepatitis (NASH)
• * Under development by Phenex and Gilead
The Pan-Omics Summit of Boston
May 21-22, 2015
Includes four co-located conferences:
1. The 5th Next Generation Sequencing
2. The 2nd Metabolomics : Advances and
Applications in Human Disease
3. Epigenomics and Novel Therapeutic Targets
4. Functional Genomics and Predictive Medicine
Yet, for the time being the global burden of liver
disease morbidity and mortality is high, may
continue to remain high and may even increase: “The Global Burden of Liver Disease: The Major Impact
of China” Hepatology 2014;60:2019-2108
Therefore the impressive
Long Journey of the last 50 years
has to continue with new important developments
regarding all levels of Hepatology and all liver diseases:
The old, the new and the emerging ones.
And for the goods of the fruitful journey to become
enjoyable worldwide, the current diagnostic deficits must
be eliminated and new therapies must become available
to all those who actually need them.