Letters to the Editor

* 2014 Lippincott Williams & Wilkins

intervention, such as height, length, or septal thickness. Nevertheless, this is the largest case series to date to identify a link between PFO and acute SMA occlusion. It reveals opportunities for investigation and management of gut ischemia and the potential to reduce graft loss because of thrombosis after intestinal transplantation. 1

Henry D. De’Ath Nikant K. Sabharwal2 Oliver Ormerod2 Anil Vaidya1 1

Oxford Transplant Centre Churchill Hospital Oxford, United Kingdom 2 Department of Cardiology

John Radcliffe Hospital Oxford, United Kingdom The authors declare no funding or conflicts of interest. Address correspondence to: Henry D De’Ath, M.R.C.S., Ph.D., Oxford Transplant Centre, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, United Kingdom. E-mail: [email protected] Received 7 May 2014. Accepted 6 June 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9806-e60 DOI: 10.1097/TP.0000000000000343

REFERENCES 1. 2.

Thompson T, Evans W. Paradoxical embolism. QJM 1930: 135Y50. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients

3.

4.

5.

6.

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with stroke. N Engl J Med 1988; 318: 1148Y52. Dao CN, Tobis JM. PFO and paradoxical embolism producing events other than stroke. Catheter Cardiovasc Interv 2011; 77: 903Y9. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984; 59: 17Y20. Windecker S, Wahl A, Chatterjee T, et al. Percutaneous closure of patent foramen ovale in patients with paradoxical embolism: long-term risk of recurrent thromboembolic events. Circulation 2000; 101: 893Y8. Meier B, Kalesan B, Mattle HP, et al. PC Trial Investigators. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013; 368: 1083.

Liver Transplant in SiblingsVA Single Center Experience xperience of liver transplantation (LT) in siblings is disseminated mainly through case reports (1Y7). We performed a chart review using the electronic Finnish Liver Transplant Registry database, which contains clinical information on every LT recipient in Finland; 886 individuals from 1982 to April 10, 2013. These 886 LT recipients were treated for the following conditions: cholestatic liver disease (29.3%), other cirrhosis (25.6%), acute liver failure (17.5%), cancer (9.9%), congenital biliary atresia (7.3%), and metabolic disease (5.4%). Every LT patient in Finland is transplanted at Helsinki University Central Hospital, to which they return regularly for follow-up visits. We identified 14 individual deceased donor LT recipients, who had at least one sibling with LT, creating a prevalence of 1.6%. The study group comprised six pairs of siblings, mean age of 38 years and mean follow-up 8.8 years (Table 1). We recorded three deaths, attributed to severe noncompliance problems, sepsis, and hepatocellular carcinoma (HCC) recurrence. Etiology that led to end-stage liver disease in all except one set of siblings was recognized as complex hereditary genetic disease. The two brothers

E

with cryptogenic cirrhosis and HCC were not diagnosed with a specific underlying liver disease. Their family history revealed that the paternal side of the family suffered from undefined liver problems. A third brother from the same family was diagnosed with liver cirrhosis and HCC. A colorectal malignancy was found, and he was deemed unsuitable for LT. ‘‘Familial biliary cirrhosis’’ patient data are shown in Table 1, 4A-D: all suffered from a cholestatic fibrotic liver disease that could not be classified as any known cholestatic liver disease. The disease could not be histologically differentiated from congenital liver fibrosis. Patients’ parents were healthy, and the patients did not have any associated abnormalities or kidney disease. All had shown first signs of the liver disease in their infancy or early childhood. The indication for LT was identical within the sibling group. The course of the disease that led to liver cirrhosis, end-stage liver disease, and ultimately to LT was similar within the sibling set, and the age at transplant were close to each other in most of the cases within the set. It seems that the presence or absence of rejection was shared between

the siblings. However, we feel that our cohort is too small to make statistically reliable conclusions, given that the liver donors were so heterogeneous. During the early post-LT course, two brothers with alpha-1-antitrypsin deficiency experienced severe neurologic complications. Each brother was subjected to calcineurin inhibitors immediately after LT, as a part of our routine immunosuppressive protocol. Both experienced severe paresthesias, motor weaknesses, and altered mental status that was defined retrospectively as posterior reversible encephalopathy syndrome (PRES). The PRES is a well known but rare complication of calcineurin inhibitors that are used for immunosuppressive medication. The incidence of PRES in nonsibling population varies between 0.4% and 6% (8); however, its incidence in siblings is not known. We expected to find that LT was caused by alcohol use disorders; however, we did not find any evidence for this phenomenon in our group. Currently, 10% of LTs in Finland are caused by alcohol liver disease (ALD). Although there is a strong hereditary component for heavy drinking behavior (9), the development of ALD does not have a genetic predisposition (10). It

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& Volume 98, Number 6, September 27, 2014

TABLE 1. Detailed demographic and liver transplantation-related data of 14 liver transplant recipients with at least one sibling a liver transplant recipient too Sex/age at LT, yr a

Indication for LT

M/4.5 Hepatoblastoma

1A

Other underlying diseases

Cyclosporine A Alive 22 M/11.5 Hepatoblastoma 1Ba

Tyrosinemia Familial adenomatous Polyposis Tyrosinemia Familial adenomatous polyposis Ulcerative colitis, celiac disease

2A

M/40

Primary sclerosing cholangitis

2B

M/47

3A

M/57

3B

M/53

4A

F/22

4B

F/31

4C

M/15

4D

F/15

5A

M/50

Primary sclerosing cholangitis Cryptogenic cirrhosis and HCC Cryptogenic cirrhosis and HCC Familial biliary cirrhosis and tubulointerstitial nephritisc Familial biliary cirrhosis Familial biliary cirrhosis Familial biliary cirrhosis Cirrhosis because of alpha-1-antitrypsin deficiency

5B

M/58

Cirrhosis because of Alpha-1-antitrypsin Alpha-1-antitrypsin deficiency, deficiency genotype PIZZ

6A

F/67

Ciclosporin A 6B

Alive F/71

Congenital liver fibrosisc 10 Congenital liver fibrosis

Time Time between between LT and first LTs, yr rejection, days 7

14

Acute rejection Post-LT diabetes at 7 mo

24 15

V Familial biliary cirrhosis

Familial biliary cirrhosis Familial biliary cirrhosis Familial biliary cirrhosis Alpha-1-antitrypsin deficiency, genotype PIZZ

V

V 4.5

Last known immunosuppressive Follow-up, medication Outcome yr

DoxorubicinMycophenolate induced mofetil, cardiomyopathy

Acute rejection within first month

Crohn’s disease V

12

Posttransplant complications

V Post transplant diabetes HCC -recurrence

Cyclosporine A

Alive

14

Mycophenolate mofetil, azathioprine Ciclosporin A

Alive

18

Alive

4.5

Tacrolimus

Alive

7.5

Sirolimus

Died

6

V

V

Tacrolimus

Alive

13

1b

V

V

Tacrolimus

Alive

12

4b

V

Post-LT diabetes

Tacrolimus

Alive

5

7b

V

Died

5.5

0.4

V

Tacrolimus, azathioprine Neurologic Mycophenolate complications mofetil, because of sirolimus tacrolimus Neurologic Sirolimus complications because of tacrolimus and cyclosporine A V Mycophenolate mofetil,

Alive

3

Alive

2.6

Died

0.1

V

7

V

V

V

Sirolimus

a

Twins. In relation to first LT. c Simultaneous liver and kidney transplant. HCC, hepatocellular carcinoma; LT, liver transplantation. b

seems plausible that ALD was not found in this study because it differs significantly from other chronic diseases recorded in this group, in which the disease prevalence in relatives is increased. We recorded that primary sclerosing cholangitis was the reason for LT in a sibling pair in this current study. According to a Scandinavian study, PSC is more frequent in first-degree relatives than that in the general population (11).

Seven previously published articles reported LT in siblings, and these totaled 25 individuals. The indications for LT in pediatric cases have been type IV glycogen storage disease (3), CriglerNajjar syndrome (2) and familial hypercholesterolemia (4). Most adult sibling LT recipients are diagnosed with amyloid metabolic disturbances (1, 6, 7). Other indications are related to altered cholesterol metabolism (5).

We conclude that the prevalence of sibling LT recipients in Finland is low. This study revealed several unique features within sibling pairs; the etiologies that led to liver cirrhosis were mostly because of complex genetic abnormalities. The course of the disease leading to liver cirrhosis and tolerance to calcineurin inhibitors within a sibling set is analogous. Based on the results of this survey, we recommend a

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Letters to the Editor

* 2014 Lippincott Williams & Wilkins

thorough review of the posttransplant course of the first LT sibling when the second sibling is opted for LT.

REFERENCES 1.

Virve S. Koljonen Heikki H. Ma¨kisalo Transplantation and Liver Surgery Clinic Institute of Clinical Medicine Helsinki University Hospital Helsinki, Finland

2.

The authors declare no funding or conflicts of interest. Address correspondence to: Heikki Ma¨kisalo, M.D., Ph.D., Division of Transplantation and Liver Surgery, Helsinki University Hospital, PO Box 340, FIN 00029, Helsinki, Finland. E-mail: [email protected] V.K. and H.M. designed the study, collected and analyzed data, and wrote the article. Received 15 April 2014. Accepted 6 June 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9806-e61 DOI: 10.1097/TP.0000000000000344

3.

4.

5.

6.

Lauro A, Uso T, Masetti M, et al. Liver transplantation for familial amyloid polyneuropathy non-VAL30MET variants: are cardiac complications influenced by prophylactic pacing and immunosuppressive weaning?. Transplant Proc 2005; 37: 2214. Schauer R, Lang T, Zimmermann A, et al. Successful liver transplantation of two brothers with crigler-najjar syndrome type 1 using a single cadaveric organ. Transplantation 2002; 73: 67. Selby R, Starzl TE, Yunis E, et al. Liver transplantation for type IV glycogen storage disease. N Engl J Med 1991; 324: 39. Kucukkartallar T, Yankol Y, Kanmaz T, et al. Liver transplantation as a treatment option for three siblings with homozygous familial hypercholesterolemia. Pediatr Transplant 2011; 15: 281. Bonatti H, Falkensammer J, Sawyer R, et al. Fat luck: three siblings requiring liver transplantation for nonalcoholic steatohepatitis. Transpl Int 2008; 21: 189. Muller KR, Padbury R, Jeffrey GP, et al. Poor outcome after liver transplantation

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8. 9.

10.

11.

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for transthyretin amyloid neuropathy in a family with an Ala36Pro transthyretin mutation: case report. Liver Transpl 2010; 16: 470. Ramirez P, De Mingo P, Andreu F, et al. Long-term results of liver transplantation in four siblings from the same family with familial amyloidotic polyneuropathy type I TTR ALA-71. Transplant Proc 1999; 31: 2489. Staykov D, Schwab S. Posterior reversible encephalopathy syndrome. J Intensive Care Med 2012; 27: 11. Whitfield JB, Zhu G, Madden PA, et al. The genetics of alcohol intake and of alcohol dependence. Alcohol Clin Exp Res 2004; 28: 1153. Ali AK, Jones JS, Bradley MP, et al. Familial predisposition to alcoholic liver disease: a case-control study. Eur J Gastroenterol Hepatol 2012; 24: 798. Bergquist A, Montgomery SM, Bahmanyar S, et al. Increased risk of primary sclerosing cholangitis and ulcerative colitis in firstdegree relatives of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2008; 6: 939.

The Serum Concentration of Tacrolimus After Ingesting Omeprazole: A Pilot Study acrolimus (TCR) is an immunosuppressant drug widely used in posttransplant organ recipients (1). Its absorption occurs principally in the duodenum and ileum (2, 3), its peak serum concentration is reached between 0.5 and 4 hr after ingestion (average 2 hr), and its absorption may be facilitated by an alkaline medium (4). Omeprazole (OMP) is a proton pump inhibitor in the parietal cells of the stomach that reaches maximum concentration between 0.5 and 3.5 hr after ingestion (average 2 hr), and because it reduces gastric acidity, it is capable of releasing more alkaline content into the duodenum (5). Pharmacologic interactions between TCR and OMP are always described primarily with respect to the common metabolic pathway (CYP3A4 and P-gp) used by both medications (6, 7), which may result in elevations of the TCR plasma concentration. However, the aim of this study was to test if the possible changes in gastric acidity induced by OMP increase the serum concentration of TCR in the short term and to determine the prevalence of such increases. To that end, a double blind, placebocontrolled pilot study was performed in 28 postrenal transplant patients regularly using TCR (mean, 0.08T0.05 mg/kg/day)

T

and OMP (20 mg/day). The OMP or a placebo was ingested every morning at 6 A.M. after fasting, and TCR was ingested 2 hr later at the doses reported

above. Blood samples were taken 2 hr after the ingestion of TCR over 4 consecutive days under both the OMP and placebo regimes. Serum concentrations

FIGURE 1. Box plots (mean, median, upper and lower quartiles, outlier and range) showing the tacrolimus serum concentration after ingesting placebo or omeprazole, demonstrating no significant difference (P90.05) between placebo and omeprazole. The individual behavior of tacrolimus concentration was also showed by dispersion graphic.

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