“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.