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Gastroenterol Hepatol Bed Bench
Gastroenterol Hepatol Bed Bench
GHFBB
Gastroenterology and Hepatology From Bed to Bench
2008-2258
2008-4234
Shaheed Beheshti University of Medical Sciences Tehran, Iran

10.22037/ghfbb.v17i3.2999
Case Report
Progressive familial intrahepatic cholestasis 3 Camouflaging as Wilson disease in a 12-year-old: a diagnostic Odyssey
Panda Kalpana 1
Pradhan Subhasis 2
Dash Mrutunjay 3
Pati Girish Kumar 4
1 Department of Paediatric Gastroenterology & Hepatology, Institute of Medical Sciences & SUM Hospital, Bhubaneswar, Odisha, India
2 Department of Gastroenterology & Hepatology, MKCG Medical College and Hospital, Berhampur, Odisha, India
3 Department of Paediatrics, Institute of Medical Sciences & SUM Hospital, Bhubaneswar, Odisha, India
4 Department of Gastroenterology & Hepatology, Institute of Medical Sciences & SUM Hospital, Bhubaneswar, Odisha, India
Reprint or Correspondence: Kalpana Panda, Department of Paediatric Gastroenterology & Hepatology, Institute of Medical Sciences & SUM Hospital, Bhubaneswar, Odisha, India.E-mail: drkalpanapanda@gmail.com
2024
17 3 320324
21 4 2024
1 6 2024
© 2024, Gastroenterology and Hepatology From Bed to Bench (GHFBB)
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article, distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/) which permits others to copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
Primary Familial Intrahepatic Cholestasis type 3 is an exceedingly rare genetic cholestatic disorder characterized by the defective hepatocanaliculr bile acid transport leading to progressive liver disease. In this case report, we describe the course of treatment for a 12-year-old kid diagnosed with Wilson disease based on Leipzig score and copper investigations. The child did not improve with chelation therapy and was subsequently genetically classified as PFIC-3. This case highlighted the caveats in Wilson disease diagnostic scoring system. The diagnostic odyssey, therapeutic interventions, and outcome of this case underscore the intricate interplay between clinical suspicion, investigative strategies, and the pivotal role of genetic testing to elucidate rare liver disorders in children.

Key Words

Wilson Disease
PFIC 3
ABCB4 gene
Chronic liver disease
Genetic testing
Cholestatic liver disease
Copper overload
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pmcIntroduction

Chronic liver diseases (CLD) in the pediatric population present diagnostic conundrums owing to the heterogeneity of etiologies, and overlapping clinical manifestations. Although the astounding development of molecular diagnostic tools over the past decade helped identify previously undiagnosed entities, it has put a tremendous burden on physicians to give accurate diagnoses to patients and families. Wilson disease (WD) is a hereditary copper metabolism illness caused by a mutation in the ATP7B gene, which leads to systemic copper excess. Potential pharmacological treatability of WD with oral chelation therapy if diagnosed early thus averting need for liver transplantation combined with its diverse clinical manifestations which can range from asymptomatic transaminitis to fulminant liver failure or decompensation, compels hepatologists to keep it as one of the clinical differentials in quite a many cases of chronic liver disease. The diagnosis of WD is based on Leipzig score which encompasses clinical features with a battery of biochemical tests including copper studies (1-3). Nevertheless, several liver disorders characterized by cholestasis, such as sclerosing cholangitis, exhibit indications of excessive copper throughout the body and display aberrant copper test results. These findings have the potential to mimic Wilson's disease (4). Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited cholestatic disorders in terms of genetic defect in hepatocanaliculr bile acid transport system that leads to progressive liver injury (5). PFIC type 3, one of the subtypes of PFIC, is attributed to mutations in ABCB4 gene (6) which in rare instances can mimic WD clinically and biochemically thus posing a diagnostic challenge for clinicians (7). Hence, we present case report of a 12-year-old patient initially considered and treated as WD, but ultimately diagnosed as PFIC-3, emphasizing the pivotal role of genetic analysis in rare liver disorders, and underscoring the potential drawbacks in the conventional diagnostic scoring system for WD especially in cases with secondary copper overload.

Case report

A 12-year-male presented to our pediatric hepatology unit with two-month history of progressively increasing abdominal distension associated with flank fullness & swelling of lower limbs for 15 days. He had previously undergone therapeutic ascitic tap for this complaint prior to his admission to our hospital. Upon further investigation, the mother disclosed that she had experienced yellowish discoloration in her urine for the previous three months. He had no history of pain abdomen, fever, haematemesis, melena, altered sleep-wake cycle or personality changes, neurological symptoms, autoimmune features like rash /joint pain, or any cholestatic symptoms like pruritus. There was no family history of liver disease or consanguinity. Child's developmental milestones were age-appropriate, and he had been previously healthy with no chronic medical conditions.

Physical examination was notable for mild pallor & icterus, b/l pedal edema, and gross ascites with hepatosplenomegaly. The liver was detected by touch 3 cm below the xiphisternum, with a hard texture and a span of 7 cm. Additionally, the spleen was found to be enormous, extending 5 cm beyond the left costal border. Examination of other systems was unremarkable. He was both stunted and underweight for his age.

Based on history & clinical examination, syndromic diagnosis of decompensated chronic liver disease with the portal hypertension was made and workup was planned for common etiologies like WD/autoimmune hepatitis/chronic viral hepatitis. He was started on supportive management such as vitamin K, 20 % albumin, and diuretics.

Laboratory investigations showed deranged liver function tests, with elevated bilirubin (Total/direct):3.3/2.8 mg/dl; alanine aminotransferase (ALT): 137U/L and aspartate aminotransferase (AST): 128U/L with low serum albumin (1.89 gm/dl) and persistent coagulopathy [International normalized ratio (INR:2.92)]. Gamma-glutamyl transferase (GGT):188U/L, and alkaline phosphatase (ALP):486U/L were mildly elevated. Complete blood count showed pancytopenia [hemoglobin:8.2 gm/dl, total leukocyte count:3200/mm3, total platelet count: 30,000/mm3] s/o hypersplenism related to portal hypertension. The right liver was diminished with an irregular margin and the USG abdomen with doppler of the splenoportal axis revealed nodularity, heterogeneous parenchymal echotexture, nodularity, caudate lobe hypertrophy with splenomegaly, and multiple collaterals with extensive ascites. Upper GI endoscopy revealed grade 2 oesophageal varices with mild portal hypertensive gastropathy. Liver stiffness measurement by transient elastography was 75 kPa suggestive of cirrhotic liver. Etiological workup for chronic liver disease showed normal immunoglobulin G; autoimmune markers and viral markers [hepatitis B & hepatitis C serology] were negative. However, Ceruloplasmin level came out to be low [9 mg/dl], raising suspicion for WD. Slit lamp examination for Kayser Fleischer (KF) ring was negative, but 24-hour urine copper excretion (UCE) was high (182 mcg/day).

Transjugular liver biopsy was scheduled for histopathology and liver dry copper estimation due to the persistent coagulopathy of the infant. However, the family declined to provide assent for the procedure. Hence, as our patient had Leipzig score of 4, the diagnosis of WD was made. Chelation therapy with D-penicillamine was initiated promptly and the dose was gradually increased to 20 mg/kg/day.

Despite adherence to chelation therapy with adequate dosing for 3 months, he did not show any improvement. Liver function tests worsened with a further decline in serum albumin, increase in transaminitis, and increase in INR. Given the lack of clinical improvement, despite adequate treatment, further investigations were pursued. Nevertheless, genetic analysis that focused on mutations in the ATP7B gene that are linked to WD produced negative results. As a result of this unexpected discovery, we were compelled to reconsider the diagnosis and workup for other rare inherited causes of CLD in children. Comprehensive genetic testing, including whole exome sequencing, was undertaken which showed a homozygous missense mutations c.2906 G>A in exon 23 of ABCB4 gene, resulting in amino acid substitution p.Arg969His, consistent with diagnosis of PFIC-3.

Following the diagnosis of PFIC-3, chelation therapy was stopped, and Ursodeoxycholic acid was started, in addition to supportive measures, such as fat-soluble vitamin supplementation & nutritional support. Despite these interventions, his clinical status continued to deteriorate with persistent ascites, increasing jaundice, and coagulopathy, highlighting the progressive nature of PFIC-3. Considering advanced liver disease and failure to respond to medical therapy, he was listed for liver transplant, currently waiting for a donor.

Table 1 Clinical, Biochemical details and genetic analysis of the 6 PFIC-3 patients published to date who mimicked Wilson Disease

Author/Year/
Country
Reference	Our patient	Shneider et al
2011, USA (8)	Ramraj et al
2012, USA (9)	Boga et al
2015, USA (10)	Bansal et al
2017, India (11)	Sticova et al
2019, Czech Republic (7)	
Age/Sex	12 yr/male	2 yr/female	Case 1: 13 yr/female	15 yr/NA	21 yr/male	11 yr/male	
Case 2: 5 yr/male	
Index presentation	Jaundice
Ascites
Portal hypertension	Failure to thrive
Firm hepato
splenomegaly	Case 1: Ascites
Hepato
splenomegaly	Fatigue
Portal hypertension	Acute on chronic liver failure	Hepato
splenomegaly
Growth failure	
Case 2: Jaundice
Hepato splenomegaly	
BIL T/D (mg/dl)	3.3/2.8	1.2/0.8	Case 1:NA/0.0	2.85/ 1.67	39.7/23.9	5.8/3.5	
Case 2: NA/0.4	
AST/ALT
(U/L)	128/137	178/402	Case 1: 85/80	141/114	177/123	1003/1180	
Case 2: 187/132	
GGT/ALP
(U/L)	188/486	405/NA	Case 1: 293/774	734/596	83/95	330/NA	
Case 2: 512/346	
Albumin (gm/dl)/INR	1.89/2.92	4.2/NA	Case 1: 2.6/	4.1/NA	2.6/5.3	3.23/1.71	
Case2: 4.5/NA	
Ceruloplasmin
(mg/dl)	9	28	Case1: 26.7	35	14	NA	
Case 2: 44.6	
KF Ring	Absent	Absent	NA	Absent	Absent	Absent	
24 hr urine copper
(mcg/day)	182	NA	Case 1: 125	342	1732 mcg/ml
(ambigous)
Mcg/day not mentioned	178	
Case 2: 66	
Liver dry copper (mcg/gm)	Not done	248	Case 1: 860	1471	NA	Liver biopsy: 914
Explant: 1867	
Case 2: 863	
Liver biopsy	Not done	Bridging fibrosis
Ductular
proliferation, moderate inflammatory infiltrate	Ballooning degeneration of hepatocytes,
portal
inflammation, micronodular cirrhosis	Portal
inflammation,
ductular reaction,
Bridging
fibrosis	Cirrhosis with Mallory Denk body in hepatocytes, copper-associated protein	Micronodular cirrhosis
cholangiopathy
periportal ductular reaction,
hepato
canalicular
cholestasis	
Hepatic inflammation, bridging fibrosis	
Genetic analysis	Homozygous missense c.2906 G>A
p.Arg969His	Compound heterozygous
Missense
p.A546D, p.R176W	Case 1: Compound heterozygous
c.2563C>T (p.Q855X)
c1283T>C (p.V428A)	Compound heterozygous
c.3218G>A (p.C1073Y)
c.984T>G (p.Y328)	NA	Compound heterozygous
c.833+1G>T
c.1798T>A	
Case 2: Compound heterozygous c.490T>G (p.W164G)
c.3081+1 G>C	
Abbreviations: NA: Not available, BILT/D: Bilirubin total/direct, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, GGT: gamma-glutamyl transferase, ALP: alkaline phosphatase, INR: International normalized ratio, KF Ring: Kayser Fleischer ring

Discussion

The diagnostic journey of our patient from initial consideration of WD to the ultimate diagnosis of PFIC-3 underscores the intricacies involved in the evaluation of pediatric patients with CLD.

CLD in pediatric populations encompass a broad spectrum of etiologies, including inherited metabolic disorders, autoimmune conditions, infectious hepatitis, and genetic cholestatic syndromes. Due to overlapping clinical characteristics and differing illness presentations, it may sometimes be difficult to distinguish between these entities. In our instance, biochemical characteristics including abnormal copper tests (high UCE and low ceruloplasmin) led to the first clinical suspicion of WD. However, no improvement in clinical symptoms and liver biochemistry after adequate chelation therapy for 3 months along with absence of pathogenic mutations in ATP7B gene prompted us for further investigation into alternative causes of CLD.

WD is an autosomal recessive disorder of copper metabolism caused by the mutations in ATP7B gene, resulting in the accumulation of copper within liver, brain, cornea, etc. Clinically, WD patient can have hepatic and/or neurological symptoms though pediatric patients usually manifest with isolated hepatic involvement, however, presentation can be highly variable, which can range from asymptomatic hepatomegaly/transaminitis to fulminant liver failure (1).

In contrast, PFIC-3 is characterized by the mutation in ABCB4 gene, encoding the multidrug resistance protein 3 (MDR3) expressed in bile canalicular membrane, which plays a crucial role in transport of phosphatidylcholine from hepatocyte to bile. Disruption of MDR3 function leads to impaired phospholipid secretion resulting in hydrophobic bile which damages the bile ducts leading to intrahepatic cholestasis (5-6). The age of disease onset is highly variable, ranging from childhood to early adulthood. Jaundice, pruritus, poor growth, fat-soluble vitamin deficiencies such as reduced bone density, steatorrhea, and, ultimately, liver cirrhosis and portal hypertension with decompensation and a distinctive biochemical feature of high GGT cholestasis are the typical manifestations of PFIC-3. However, our patient did not show any cholestatic features, such as pruritus during the whole clinical course, although cholestatic markers like alkaline phosphatase and GGT were mildly elevated. In hindsight, this was a missed clue about possibility of cholestatic etiology. Albeit, the absence of any cholestatic symptoms like pruritus along with deranged copper studies precluded us from considering PFIC-3 as a possibility in the beginning.

Pediatric hepatologists are compelled to keep WD as one of the clinical differentials in quite a few cases of CLD in terms of the disease's diverse clinical manifestations, which can range from asymptomatic transaminitis to fulminant liver failure or decompensation, as well as its potential pharmacological treatability with oral chelation therapy if diagnosed early thus preventing the need for liver transplantation. However, Leipzig score, used to diagnose WD (a score of ≥ 4) has certain caveats which may result in misdiagnosis as highlighted in our patient (1).

It is now a proven fact that UCE, and liver copper content [two of the components of Leipzig score] can increase in many cholestatic liver diseases such as sclerosing cholangitis in terms of secondary copper overload. The suggested causes of the secondary copper overload in cholestatic liver disorders are the disturbance of copper transport via bile caused by duct collapse and a failure in hepatic lysosomal activity. Sood et al. published a series of 4 patients who were initially diagnosed as WD based Leipzig score which was subsequently proven to be cases of small duct sclerosing cholangitis (4). Similarly, serum ceruloplasmin, most common and initial screening biomarker used for WD diagnosis could be falsely low if there is hypoalbuminemia due to advanced liver disease affecting synthetic function. Given that KF rings are seen in around half of individuals with hepatic impairment, their presence or absence does not provide useful information for diagnosing or ruling out the condition. Sood et al. concluded that borderline serum ceruloplasmin values (i.e. 10-20 mg/dl) and UCE (40-100 mcg/day) might result in overdiagnosis of WD under current international guidelines (4). Recommended UCE cutoffs for diagnosing WD in adults and pediatric patients are >100 mcg/day and >40 mcg/day, respectively. However, AASLD in their latest guideline acknowledged that secondary copper overload can cause a higher urine copper excretion than normal leading to the misdiagnosis of WD though ceruloplasmin usually remains normal in these patients (1). Nonetheless, UCE of our patient was 178 mcg day which is well above the recommended cutoff. Moreover, his ceruloplasmin was low <10 mg/dl; unlike previous published case reports of PFIC 3 mimicking WD.

Five case reports documenting 6 patients (1 adult, 5 pediatric) were published to date where an initial diagnosis of WD was contemplated based on biochemical tests, which turned out to be PFIC 3 after genetic testing (Table 1). A 2-year female with chronic liver disease, who was initially diagnosed as WD due to elevated liver copper levels, was subsequently genetically diagnosed as PFIC 3 in the first case report published in 2011 (8). Ramraj et al. reported two children of age 13 years and 5 years who presented with chronic liver disease, diagnosed as WD based on high UCE and liver copper, but did not show any improvement with chelation and subsequently underwent genetic analysis; only to be showed as cases of PFIC-3 (9). Two such identical cases were reported by Sticova et al in a 11-year-male and by Boga et al in a 15-year old child (7, 10). Bansal et al reported a 21-year-male with acute on chronic liver failure who initially was considered WD and underwent liver transplant. On the other hand, the histology of the explant liver showed that MDR3 expression was absent, suggesting PFIC-3. Two of his other siblings later had pruritus, and a liver biopsy from them revealed that MDR 3 expression was absent, which is indicative with PFIC-3 (11). The initial impression of WD in these reports may be questioned because, except last case, all other cases had ceruloplasmin >20 mg/dl, along with high GGT & ALP. However, in our case, the ceruloplasmin was very low (9 mg/dl) and GGT /ALP was only mildly raised. Very low ceruloplasmin of our patient correlates with his decompensated liver disease status with hypoalbuminemia.

Genetic testing plays a pivotal role in the diagnosis of inherited liver diseases, particularly in cases with atypical presentations or inconclusive biochemical findings. The absence of pathogenic mutations in the ATP7B gene in our case necessitated additional research into alternative genetic causes. Timely recognition of PFIC-3 in our patient facilitated appropriate management and prompt referral for liver transplantation.

In conclusion, our case highlights the importance of considering the alternative diagnoses, and utilizing advanced genetic testing modalities to establish an accurate diagnosis, especially if a patient initially considered to be WD is not showing improvement despite adequate chelation dose & compliance.

Conflict of interests

The authors have no conflicts of interest to declare.
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References

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