” Systematic “protocol” evaluations at each visit, liver tissue examinations at 6 month intervals, uniform treatment schedules, predefined responses to disease behavior, regular surveillance schedules using mailed serum specimens,

GSK3 inhibitor serum and liver tissue banks, and commitment to indefinite patient follow-up were the manifestations of this “tenacity.” I remain convinced that rigid adherence to protocol and compulsive follow-up are essential components of successful clinical investigation (Table 1). Bill Summerskill died suddenly in March 1977, and I was abruptly launched solo into the realm of CALD. Life-saving therapy had now been established by three controlled clinical trials; the disease was rare; funding sources were limited or uninterested,

and my principal initial concern was that there was nothing more to study.21,39,40 The practical clinical problems that required answers became obvious quickly through routine patient care, and they generated a compelling urgency for further clinical studies. Remarkable work from Meyer zum Buschenfelde’s group in Mainz, Germany,41-44 and Roger Williams’ group in London, England,45-49 invigorated the concept of autoimmune hepatitis, and I suddenly realized anew that I was in an exciting place at an exciting time. The first objective was to describe the clinical phenotype of autoimmune hepatitis and to distinguish it from other diseases. This was done by describing its autoantibodies,50 Quisqualic acid histological manifestations,51,52 clinical presentations,53-55 and response to corticosteroid treatment.56-58 The ITF2357 price disease had to be distinguished from systemic lupus

erythematosus59 and chronic viral hepatitis60; it had to be released from the early restrictive requirement for 6 months of disease activity61; subtypes based on mutually exclusive serological markers had to be explored62-64; and it had to accommodate patients with nonclassical manifestations.65 This was the era of serological exploration, and collaborations with Mikio Nishioka,66-70 Francesco Bianchi,71,72 Michael Manns62-64 and their coworkers were essential to understand the nature and clinical significance of antinuclear reactivities, including antibodies to ribonucleoproteins, histones, single-stranded DNA and doubled-stranded DNA, antibodies to actin, antibodies to liver kidney microsome type 1 (anti-LKM1), antibodies to soluble liver antigen (anti-SLA), and antimitochondrial antibodies in autoimmune hepatitis. These efforts complemented studies performed elsewhere, and they supported concepts of an acute autoimmune hepatitis,54 two serologically distinct forms of the disease,73 variant syndromes characterized by antimitochondrial antibodies,74 bile duct changes,75-79 or concurrent viral infection,80-82 and a seronegative state frequently misclassified as cryptogenic chronic hepatitis.