Karin F. Kok, MD

Heterozygosity for Alpha-1-Antitrypsin Deficiency: underestimated in chronic liver disease?

The role of heterozygosity for Alpha- 1-Antitrypsin (AAT) alleles in patients with chronic hepatitis C is unclear. There is some evidence suggesting an increased prevalence of heterozygous AAT carriers in HCV, however, it is unclear how this affects treatment success. The aim of our study was to investigate the (1) prevalence of AAT heterozygosity among 2 HCV cohorts and (2) its effect on treatment outcome. We performed a retrospective cohort study using two different cohorts. Cohort 1 consists of 678 German HCV patients, while cohort 2 consists of 370 Dutch patients. A total of 243 HCV patients were part of a clinical trial (treatment with amantadine or placebo, in combination with PEGinterferon a-2b and weight-based ribavirin) while 37 HCV patients received standard combination therapy. We analyzed AAT status using iso-electropheresis of plasma (cohort 2), or direct sequencing of the AAT gene (cohort 1). In addition we measured AAT serum levels (cohort 2). In total we included 1048 HCV patients; 987 were wildtype (94%), while 6% were heterozygous for a mutant AAT allele (41 Pi MS, 20 Pi MZ). Mean serum levels (370 patients) were lower in heterozygous carriers (1.68 g/l vs. 1.36 g/l), (p<0.05). Sustained viral response (SVR) was reached in 70.4% of 257 treated wildtype patients but only in 57% of the 23 AAT heterozygous patients (or 1.8 (95%CI 0.77-4.4), p=0.08). We found a heterozygosity rate of 0.06 in line with control populations. Serum AAT levels from heterozygous HCV patients are significantly lower compared to wildtype patients, although they do not discriminate on an individual level. Finally, AAT heterozygotes had worse outcomes on HCV combination therapy.

1988 - 1994 Secondary school (VWO), Pius X College in Almelo, The Netherlands
1998 Student Exchange Programme with Matki Polki Obstetric Hospital (Lòdz, Poland)
2000 MD degree (cum laude): Catholic University Nijmegen, The Netherlands
2000 - 2004 Trainee in internal Medicine: Rijnstate Hospital Arnhem, The Netherlands
(supervisor: dr. R. van Leusen)
2005 - 2006 Trainee in Gastroenterology: Rijnstate Hospital Arnhem, The Netherlands
(supervisor: dr. P.J. Wahab and dr. R.A. de Vries)
2007 Trainee in Gastroenterology, University Medical Center, Nijmegen, The Netherlands
(chair: prof. dr. J.B.M.J. Jansen)

Research activities:
2000 K.F. Kok, H. Verbruggen, A. Pennings, P. Jacobs, I. Nováková. Differences in the number of reticulated platelets and alpha-granule release between ITP and MDS. Abstract and poster presentation. Dutch Society for Haematology.
2001 K.F. Kok, K. Peters, G. den Hartog, P.J. Wahab, J.W.R. Meijer, A. Huisman, R.A. de Vries. Acute fatty liver and intrahepatic cholestasis in pregnancy; an unusual combination. Abstract and oral presentation. Dutch Society for Internal Medicine.
2005 K.F. Kok, P.J. Wahab, R.A. de Vries. Heterozygosity for Alpha-1-Antitrypsin deficiency as a cofactor in the development of chronic liver disease. Ned Tijdschr Geneeskd 2005;149:2057-61
2006 K.F. Kok, R.A. de Vries. Acute pancreatitis in a hepatitis C positive patient following treatment with peginterferon alfa-2b and ribavirin. Ned Tijdschr Geneeskd 2006;150:681-3

K.F. Kok, M.S. Goerres, J.W.R. Meijer, R.A. de Vries, C.J.J. Mulder, P.J. Wahab. Marsh II enteropathy: who is gluten sensitive and needs treatment? Poster presentation. XII international celiac disease symposium, New York
2007 K.F. Kok, P.J. Wahab, R.H.J. Houwen, J.P.H. Drenth, R.A. de Man, B. van Hoek, J.W.R. Meijer, F.L.A. Willekens, R.A. de Vries. Heterozygous alpha-1 antitrypsin deficiency as a co-factor in the development of chronic liver disease, a review. Neth J Med. 2007 May;65(5):160-6

Karin F. Kok, MD< br/> University Medical Center
Department of Medicine
Division of Gastroenterology and Hepatology
P.O. Box 9101
6500 HB Nijmegen
The Netherlands
Telephone: +31 (24) 3614760
Fax: +31 (24) 3540103