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Cross-sectional analysis of progressive familial intrahepatic cholestasis in Puerto Rican children.

The Puerto Rican ancestry is a mix of African, European, and American Indian, "los Tainos." Several genetic diseases, including Hermansky-Pudlak syndrome (HPS 1 and 3), are found with relatively high frequency on the island of Puerto Rico (1)(2). Steel syndrome (3) and primary ciliary dyskinesia-11 (4) have also been described as founder mutation events that segregate in the Puerto Rican population. Spondylocostal dysostosis is also more prevalent on the island than anywhere else, comprising 49% of described cases (5).

Clayton first described severe fatal intrahepatic cholestasis in 6 members of 4 sibships of the Old Order Amish (6). To our knowledge, the term "progressive familial intrahepatic cholestasis" was first used by Ballow in his 1973 report (7). In that report, 2 brothers of unrelated Puerto Rican parents who developed early-onset jaundice, pruritus, malabsorption, and rickets were described. The brothers both had conjugated hyperbilirubinemia with elevated bile acids. At that time, a defect in the hepatic excretory mechanism for bile acids was postulated, with a possible autosomal recessive pattern of inheritance.

Leevy described 4 Puerto Rican sisters who had prolonged recurrent cholestasis of pregnancy, accompanied by pruritus with every pregnancy (8). In addition, their pruritus was provoked by oral contraceptives. Two had gallstones and 2 had increased hepatic copper deposition. A genetic basis for their disorder is highly likely, perhaps MDR3 (ABCB4) deficiency, which has been associated with gallstones and intrahepatic cholestasis of pregnancy, among other problems (9). Leevy's report preceded the molecular identification of MDR3 deficiency.

In this report we describe 10 children from Puerto Rico with elevated gamma-glutamyl transpeptidase (GGTP) cholestasis. We explored aspects of their clinical presentations as well as their responses to ursodeoxycholic acid (UDCA) therapy.


A cross-sectional analysis including a review of existing medical records and the conducting of personal interviews were performed in patients with chronic cholestasis at "Hospital Pediatrico Universitario" in San Juan, Puerto Rico. Patients were identified by their primary gastroenterologists for possible enrollment in the study. For each, an informed consent was obtained at the time of the appointment with his or her primary gastroenterologist. Exclusion criteria as well as a data collection questionnaire were adapted with permission from the protocol for the NIH/NIDDK-sponsored study of the Childhood Liver Disease Research Network (ChiLDReN): Longitudinal Study ofGenetic Causes of lntrahepatic Cholestasis (NCT00571272). The study had 2 sets of inclusion criteria, with the first consisting ofevidence of liver disease and the second consisting of evidence of cholestasis; to take part in the study a given patient had to meet a minimum of 1 condition in each set. Criteria were as follows:

Set 1: clinical or biochemical hepatic abnormalities for at least 6 months; clinical or histological stigmata of liver disease; a sibling affected by progressive familial intrahepatic cholestasis or benign recurrent intrahepatic cholestasis; recurrent and episodic cholestatic disease (without identifiable cause) occurring on more than 2 occasions, the episodes of which are separated by at least 3 months.

Set 2: a fasting serum bile acid level greater than 3x the upper limit of normal (ULN) for age; a direct or conjugated bilirubin level greater than 2mg/dL; fat soluble vitamin deficiency without identifiable cause; a GGTP level greater than 3x ULN for age; intractable pruritus secondary to liver disease.

Individuals with other known causes of chronic cholestasis were excluded. The study was approved by the IRBs of both the University of Puerto Rico Medical Sciences Campus and the University of Pittsburgh School of Medicine. Informed consent/assent was obtained from all of the participants and/ or their parents/guardians. The clinical data were collected by reviewing medical records and from the personal interviews conducted at the scheduled 1-time visit with the participants' primary gastroenterologists. The clinical information included family history; age and clinical presentation at the onset of symptoms; disease evolution; diagnostic workup including bloodwork, imaging, liver biopsy findings; and previously attempted therapeutic measures (with a focus on the use of UDCA) and surgical interventions such as partial external biliary diversion or liver transplantation. The clinical onset of disease was determined based upon each patient's history; the initial laboratory data included the first testing done after that patient's referral to their pediatric gastroenterologist, while the last set was the one obtained closest to and prior to the time of each participant's enrollment. Liver biopsy pathology results were extracted from reports without an independent review of histology. Informed consent was obtained for 23 patients. Thirteen participants met the inclusion criteria. As the vast majority of participants had a GGTP level of more than 100 IU/L, this analysis was focused on the 10 enrolled participants making up that majority.

The differences in the biochemical parameters were assessed using standard statistical parameters, unpaired t-test results were used.


This cohort included 10 children with high GGTP cholestasis, operationally defined as having a GGTP level greater than 100 IU/L at initial testing (prior to UDCA treatment) (Table 1). The relevant clinical information from the review of the medical records and the medical interviews is summarized in Tables 1 and 2. Participants had been followed for a minimum of 6 months at the time of study enrollment, with a median follow-up of 7.5 years after the clinical presentation. Of note 2 of the participants, siblings 5 and 6, were referred as low GGTP cholestasis, although their GGTP measurements prior to instituting UDCA therapy were not available for review. One of these siblings had a GGTP level over 100 IU/L while receiving UDCA, and as such both siblings were classified as having high GGTP cholestasis. These 2 children had a poor response to UDCA and ultimately required partial external biliary diversion. They had a partial response to surgery, and over 5 to 10 years developed end-stage liver disease manifesting with variceal hemorrhage and ascites. They underwent liver transplantation at 11 and 12 years of age, respectively.

Response to UDCA could be assessed in 8 children. For this analysis a significant improvement ("normalization") after the use of UDCA was defined as an ALT < 40 IU/L and a GGTP < 100 IU/L. The liver profile in six patients normalized, and in two patients improved in response to UDCA. (Table 3). Overall, differences in both ALT and GGTP in response to UDCA therapy were statistically significant (ALT before: 182 [+ or -] 61; and after: 30 [+ or -] 15; p-value<0.0001; GGTP before: 353 [+ or -] 192; and after: 21 [+ or -] 13; p = 0.0005).

The family histories revealed that 1 participant had 1 set of consanguineous grandparents, 2 participants had positive family histories for gallstones, and 1 had a grandparent with decompensated liver disease of unknown etiology. In this study, participant 3 had increased copper deposition on liver biopsy, and participant 9 suffered from pruritus during pregnancy, with complete resolution after delivery.


In this study 10 Puerto Rican patients with high GGTP chronic intrahepatic cholestasis are described. Genetic mutations of ABCB4 may lead to chronic cholestasis, chronic "hepatitis," cryptogenic cirrhosis, intrahepatic lithiasis, gallstones, intrahepatic cholestasis of pregnancy (ICP), or progressive familial intrahepatic cholestasis type 3 (PFIC3), all of which are typically associated with elevated GGTP levels (9). ICP associated pruritus usually resolves after delivery (10). Patients with PFIC3 have elevated serum GGTP and their clinical presentation may vary; including asymptomatic chronic elevations in liver biochemistries, jaundice, pruritus, hepatosplenomegaly, and features of cirrhosis and portal hypertension. These clinical features were observed in this cohort.

In patients with PFIC3, especially in individuals with "mild" mutations in ABCB4, UDCA may be very effective, leading to improvements in both biochemical parameters and symptoms (11). UD CA is hypothesized to work by altering the biliary bile acid composition in favor of the less toxic hydrophilic bile acids

(9). In general, the UDCA response in this cohort suggests that ABCB4 (MDR3) deficiency, a relatively rare genetic disorder, may be more prevalent than previously suspected in Puerto Rico.

Elevated hepatic copper has been described in patients with mutations in the ABCB4 gene after initially been incorrectly diagnosed with Wilson's disease (WD), as we observed in 1 of our subjects. Shneider reported on a 2-year-old patient who presented with cirrhosis and copper overload secondary to heterozygous missense mutations in the ABCB4 gene (12). Ramraj described 2 patients with elevated hepatic copper. Both patients had full gene sequencing for both the ABCB4 gene and the ATP7B gene (WD gene) (13). Both patients were compound heterozygous for deleterious mutations in the ABCB4 gene, with no mutations in ATPB7.

This report is limited by the small number of cases and the lack of general availability of clinical genotyping. Despite these limitations, the investigations suggest that ABCB4 deficiency may be prevalent amongst genetic disorders in the Puerto Rican population. Definitive diagnosis will require genetic testing. Eight of the 10 patients may benefit from selective ABCB4 gene sequencing, as they presented with the classic clinical signs for MDR3 deficiency with adequate response to UDCA. On the other hand, the 2 sisters may have a different, and possibly more aggressive, familial cholestatic disease. Whole exome sequencing may be an important diagnostic approach for them. A systematic investigation of the genetic causes of specific forms of chronic liver disease in Puerto Rico is warranted.


Dellys Soler and Benjamin Shneider were at the University of Pittsburgh School of Medicine, Pittsburgh, PA, during the initiation of and data collection phase of this investigation. Benjamin Shneider received an investigator-initiated award (drug only) from Hyperion Therapeutics for the investigation of intrahepatic cholestasis.


(1.) McKusick VA. Hermansky-Pudlak Syndrome 1 [ website]. November 26, 2014. Available at: Accessed November 11, 2014.

(2.) Hamosh A. HPS3 Gene [ website]. July 16, 2001. Available at: Url: Accessed November 11, 2014.

(3.) Rasmussen SA. Steel Syndrome [ website]. April 30, 2013. Available at: Url: Accessed November 11. 2014.

(4.) Kniffin CL. Ciliary Dyskinesia, Primary, 11 [ website]. March 5, 2009. Available at: Url: Accessed November 11, 2014.

(5.) McKusick VA. Spondylocostal Dysostosis 2, Autosomal Recessive [ website]. May 21, 2004. Available at: Url: http://www.omim. org/entry/608681. Accessed November 11. 2014.

(6.) Clayton RJ, Iber FL, Ruebner BH, McKusick VA. Byler's disease: Fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child 1969;117:112-124.

(7.) Ballow M, Margolis CZ, Schachtel B, Hsia E. Progressive Familial Intrahepatic Cholestasis. Pediatrics 1973;51:998-1007.

(8.) Leevy CB, Koneru B, Klein KM. Recurrent familial prolonged intrahepatic cholestasis of pregnancy associated with chronic liver disease. Gastroenterology 1997;113:966-972.

(9.) Trauner M, Fickert P, Wagner M. MDR3 (ABCB4) Defects: A Paradigm for the Genetics of Adult Cholestatic Syndromes. Semin Liver Dis 2007;27:77-98.

(10.) Sundaram SS, Sokol RJ. The multiple facets of ABCB4 (MDR3) deficiency. Curr Treat Options Gastroenterol 2007;10:495-503.

(11.) Gonzales E, Davit-Spraul A, Baussan C, Buffet C, Maurice M, Jacquemin E. Liver diseases related to MDR3 (ABCB4) gene deficiency. Front Biosci (Landmark Ed) 2009;14:4242-4256.

(12.) Shneider BL. ABCB4 Disease Presenting with Cirrhosis and Copper Overload-Potential Confusion with Wilson Disease. J Clin Exp Hepatol 2011;1:115-117.

(13.) Ramraj R, Finegold MJ, Karpen SJ. Progressive Familial Cholestasis Type 3: Overlapping Presentation with Wilson Disease. Clin Pediatr (Phila) 2012;51:689-691.

Dellys M. Soler, MD *; Antonio I. Del Valle, MD ([dagger]); David Fernandez-Lube, MD ([dagger]); Benjamin L. Shneider, MDI

* Children's Healthcare of Atlanta, GA; ([dagger]) School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico; ([double dagger]) Texas Children's Hospital, Houston, Texas

The authors have no conflicts of interest to disclose.

Address correspondence to: Dellys M. Soler, MD, Children's Healthcare of Atlanta, 2015 Uppergate Drive NE Atlanta, GA 30322. Email:
Table 1. Initial clinical data in 10 patients with high GGT cholestasis

Case     Sex age    Clinical             Age            ALT
number   at onset   presentation         presentation

1        M/8m       Hepatomegaly,        8m             98
                      and abnormal
                      liver panel
2        F/5m       Pruritus, abnormal   9m             118
                      liver panel

3 *      M/5y       Hepatosplenomegaly   7y             268

4        F/12y      Abnormal liver       13y            165

5        F/6m       Pruritus             4y             47

6        F/6m       Pruritus             10y            37

7        M/3 y      Abnormal liver       3y             226

8 **     F/13y      Abnormal liver       13y            135
                      panel and
9        F/9y       Abnormal liver       9y             219

10       F/14y      Abdominal pain,      14y            223

Case     AST   TB    DB    GGTP Liver Biopsy (age)

1        146   0.7   0.1   223   N/D

2        111   1.1   0.8   313   Canalicular
                                   with ductular
                                   fibrosis (10m)
3 *      268   1.4   --    650   Cirrhosis and
                                   amount of
4        110   0.7   0.2   653   Proliferation of
                                   bile ductules
                                   at periphery.
                                   metaplasia of
                                   fibrosis (14y)
5        75    1.7    1    126   Mild portal
                                   Signs of early
                                   Mild bile
                                   with number
                                   of bile ducts
                                   with no
6        56     4    --    33    Micronodular
                                   cirrhosis with
                                   scant patchy
                                   and canalicular
                                   positive for
                                   CD10/GGT found
                                   along few
                                   canaliculi but
7        99    0.6   --    154   Portal areas
                                   with chronic
                                   cells with
                                   Normal bile
                                   ducts (3y)
8 **     147    6    --    230   N/D
9                    --    290   No interface
                                   hepatitis or
                                   fibrosis was
                                   positive by
                                   Paucity of
                                   bile ducts with
10       188   0.6   --    310   N/D

* patient 3 had an initial platelets count of 102x10^3 [micro]L and a
ceruloplasmin of 67 mg/dL; ** patient 8 had an initial platelets
count of 78x10^3 [micro]L; Legend (for table 1 and 2): ALT=alanine
aminotransferase (U/L), AST= aspartate aminotransferase (U/L),
TB = total bilirubin ([micro]mol/L), DB= direct bilirubin
([micro]mol/L), GGTP = gamma-glutamyl transpeptidase (U/L),
BSEP = bile salt export pump, MRP2 = multidrug resistance-associated
protein 2, OLT = orthotopic liver transplant, N/D = not done.

Table 2. Last clinical data in 10 patients with high GGT cholestasis

Case       UDCA         Age          ALT   AST   TB    DB     GGTP
number   initiation

1          12m          17m          36    41    --    --     13
2          11m          12m          35    --    0.7   --     24
3          7y           8y           25    37    0.3   --     48
4          14y          14y10m       20    30    0.5   0.15   18
5          infancy      18y          24    28          --     15
6          infancy      17y          13    17    3     0.6    14
7 *        4y           13y          12    24    0.5   --     12
8 **       13y          19y          24    26    0.8   --     25
[degrees]  10y          18y          59    35    0.3   --     8
10         14y          20y          37    49    1.8   0.4    54

* last platelets count was 274x10^3 [micro]L, ** last platelets count
was 89x10^3 [micro]L; last platelets count was 33x10^3 [micro]L,
albumin 4.5g/dL

Table 3. Changes in serum alanine aminotransferase and
gamma-glutamyl transpeptidase measurements after the use of
ursodeoxycholic acid.

Case Number   Initial   Final   Initial   Final
              ALT       ALT     GGTP      GGTP

1             98        36      223       13
2             118       35      313       24
3             268       25      650       48
4             165       20      653       18
5 *           N/A       N/A     N/A       N/A
6 *           N/A       N/A     N/A       N/A
7             226       12      154       12
8             135       24      230       25
9             219       59      290       8
10            223       37      310       54
Mean (n=8)    182       30      353       21
SD (n=8)      61        15      192       13

Legend: ALT = alanine aminotransferase (U/L), GGTP = gamma-glutamyl
transpeptidase (U/L), SD= standard deviation. * Data is not available
for subjects 5 and 6.
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Article Details
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Title Annotation:BRIEF REPORTS
Author:Soler, Dellys M.; Del Valle, Antonio I.; Fernandez-Lube, David; Shneider, Benjamin L.
Publication:Puerto Rico Health Sciences Journal
Article Type:Survey
Date:Dec 1, 2016
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