Comorbidity between progressive familial intrahepatic cholestasis and atopic dermatitis in a 19-month-old child

Abstract

Atopic dermatitis (AD) is the most common chronic skin disease in children, with an increasing prevalence in the past three decades. Adequate treatment is prescribed for individual patient based on symptoms and disease severity. However, further underlying diagnosis should be researched when therapeutic strategies for symptoms fail and skin lesions and pruritus persist. We reported herein the case of a 19-month-old infant with a history of AD unresponsive to treatment due to the type 2 progressive familial intrahepatic cholestasis (PFIC). A new homozygous mutation of the ABCB11 gene was found. The severe pruritus, the early onset jaundice, poor growth and raised transaminase levels with normal gamma glutamyl transpeptidase have led to the suspicion of PFIC. The presence of severe AD and intrahepatic chronic cholestasis, both pruritus associated, could delay a proper diagnosis. To our knowledge, for the first time, a case of comorbidity between type 2 PFIC and AD-like disease had been described.

Background

Atopic dermatitis (AD) is a complex often relapsing inflammatory skin disorder in childhood; AD also involves adults and the estimate prevalence ranged from 2.1% to 4.9% across countries.^{1 2 3}

The diagnosis of AD requires the presence of three features: (1) pruritus; (2) typical morphology and distribution of the eczema; and (3) chronic relapsing course.⁴ AD is caused by a combination of genetic and environmental factors; therefore, skin inflammation is determined by both allergic and non-allergic mechanisms. In addition, severity of AD could be determined by frequency and type of mutations in genes involved in skin barrier function (ie, FLG – FLG2-SPINK5).⁵

The most important risks associated with the development of AD are (1) family history of atopy, (2) high total and specific serum IgE and (3) the loss of function mutations in the fillagrine FLG gene. Basically there are three treatment measures for AD: investigations and elimination of exacerbating factors, proper correction of skin dysfunctions (skin care) and pharmacotherapy. The treatment is prescribed adequately for each individual patient using Patient-Oriented SCORing Atopic Dermatitis (PO-SCORAD) index.

However, underlying or further diagnosis should be considered when therapeutic strategies for AD fail and eczema lesions or pruritus persist.

We reported the case of a 19-month-old infant with a history of unresponsive AD and chronic pruritus due to a rare inherited liver disease belonging to the group of progressive familial intrahepatic cholestasis (PFIC). A new homozygous mutation of the ABCB11 gene associated with type 2 PFIC due to paternal uniparental disomy (UPD) of chromosome 2 was discovered. This new genetic variant and the comorbidity between PFIC and AD are not described before in the literature.

Case presentation

We described herein the case of a 19-month-old Caucasian infant girl with a history of widespread and severe pruritus and moderate-severe AD started from fifth month of life.

The patient was born at term, from a non-consanguineous, healthy parents. Birth weight and length were adequate for gestational age. She had no postnatal complications, but her parents reported a delayed meconium passage by the second day of life. She was bottle fed until the 14th month of life and complementary feeding was not completed. A history of constipation and poor growth was reported since early months of life.

On clinical examination, the girl’s weight and height were under the fifth percentile, but in line with genetic target. She had a xerotic skin and severe eczema-like lesions on the forehead, periorbital area, perioral area, nose root, lips, periauricular area, trunk and upper/lower limbs (figures 1 and 2). Dennie-Morgan folds on the patients face were absents. The PO-SCORAD index calculated, based on the evaluation of the eczema extension, objective symptoms (erythema, oedema, exudation, scratching injuries, lichenification) and subjective symptoms (itch and sleep disorders), was greater than 40.

Figure 1.

Severe eczema-like lesions on the forehead, periorbital area, perioral area, nose root, lips and periauricular area.

Figure 2.

Severe eczema-like lesions on the foot.

Titre of serum IgE was normal. Skin prick test and specific IgE (IgEs) for house dust mites, eggs, cow’s milk and peanuts were performed and resulted negative. Diagnosis of AD was claimed on clinical basis and treatment was started based on skin hydration, moisturisers and topical corticosteroids (methylprednisolone aceponate ointment) for 3 months; a short course (6 days) with oral amoxicillin and/or oral H1-antihistamine was prescribed for two times due to worsening of symptoms.

After this period on the follow-up examination, skin lesions improved while itching persisted. She appeared extremely irritable with widespread lesions from scratching, especially on her back and abdomen. She also presented moderate jaundice, intestinal meteorism and mild hepatomegaly. Weight and height were persistently under the fifth percentile.

Investigations

First investigations showed normal values of complete blood count, blood glucose level, kidney function values, immunoglobulin, total cholesterol, high-density lipoprotein, triglycerides and urine analysis. Liver function tests revealed hypertransaminasemia, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased to 4 and 6.5 × upper limit of normal (ULN), gamma glutamyl transpeptidase (GGT) were normal, whereas alkaline phosphatase (ALP) was 2.2 × ULN. Total bilirubin value was 4.3 × ULN and direct bilirubin level was up to 85% of the total value. Prothrombin time and partial thromboplastin time were normal.

Evaluation of thyroid hormones showed a mild subclinical hypothyroidism for which L-T4 treatment was not indicated. Serum IGF-1 concentrations and bone age were accordant to chronological age. IgG class antibodies against native gliadin (AGA) were mildly increased, whereas IgA class anti-transglutaminase and anti-endomysial antibodies were negative.

A liver disorder, more specifically a cholestasis caused by genetic factors, was suspected and she was closely monitored and investigated accordingly. Serological tests for Epstein-Barr virus, cytomegalovirus, hepatitis B virus, hepatitis C virus, hepatitis A virus and adenovirus were normal, as well as Alpha1-antitrypsin and ammonia serum level. Sweat chloride test was performed. Evaluation of vitamins A, E and K showed slightly lower values, while serum bile acids were raised (278 µmol/L).

Further investigations with abdominal ultrasound demonstrated normal dimensions and echostructure of liver and spleen. Liver biopsy showed severe cholestasis with widespread acute metaplasia of hepatocytes and canalicular biliary thrombi, focal gigantocellular transformation of hepatocytes, increased portal veins numbers and hypertrophy of Kuppfer’s cells. It also described marked porto-periportal fibrosis and periacinar fibrosis, poor interlobular bile ducts and periportal biliary metaplasia of hepatocytes.

Gene analysis was performed by DNA exome next generation sequencing and discovered a homozygous mutation of the ABCB1 1 gene (c.2494C>G; p.Arg832Gly), associated with type 2 PFIC (PFIC2). The heterozygosis of parents for the defect found in the affected patient did not confirm the recessive inheritance of the disease because the patient’s mother was not a carrier of the mutation. Further analysis confirmed that the patient had a paternal UPD of chromosome 2, responsible for homozygosity of mutation.

Treatment

Treatment of PFIC2 which consisted of nutritional support (adequate calories intake, supplementation of fat-soluble vitamins and medium chain triglycerides) associated with drugs to control pruritus and improve quality of life (ursodeoxycholic acid, rifampicin, cholestyramine and H1-antihistamine) was started with great improvement of itching, especially during the daytime.

Outcome and follow-up

After 6 months at the follow-up examination, the patient showed mild gain growth (weight is on upper the 15th percentile and height on the 5th percentile) and good clinical conditions.

She had persistent xerotic skin but no longer jaundice. AD exacerbations were treated with skin hydration, moisturisers and topical corticosteroids.

Discussion

PFIC is a group of autosomal recessive genetic disorders. PFIC is caused by a deficiency in bile secretion and presents with intrahepatic chronic and progressive cholestasis, usually during infancy or childhood resulting in end-stage liver disease, death or liver transplantation. The incidences are about 1 per 50 000 to 1 per 100 000 births, although exact prevalence is not known.⁶ The disease affects both male and female equally all over the world.⁷

Three distinct types are recognised, which differ in the genetic defect involved in bile transport. Genes encoding the protein ATP8B1, the protein ABCB11 and the multidrug resistance class III protein are involved, respectively, in types 1, 2 and 3. The age of onset and severity are variable, typically the neonatal period in PFIC2, infancy in PFIC1 and adulthood/late adolescence in PFIC3.

PFIC2 was historically known as Byler’s syndrome and it is due to the mutation in the ABCB11 (ATP binding cassette (ABC) family B, member 11) gene encoding BSEP, located on chromosome 2 (2q24). BSEP is the main exporter of bile acids from hepatocyte to canaliculi against a concentration gradient transporter protein. It is expressed at the canalicular membrane of hepatocyte. Genetic mutations (insertion, deletion, nonsense and splicing) determine the premature truncation of protein or total failure of protein production.^{6 7}

These deficits in BSEP synthesis or function reduce bile salt secretion followed by decreased bile flow, accumulation of bile salts in hepatocytes and hepatocellular damage.

The major form of clinical presentation is pruritus. It is the most debilitating symptom, leading to cutaneous mutilation, loss of sleep and irritability. Cholestasis and jaundice are severe and persistent in type 2 in comparison to type 1, which has recurrent jaundice initially and permanently later in the disease course.⁶ Extrahepatic symptoms such as diarrhoea or acute pancreatitis are more common in type 1 PFIC. Both the above conditions are associated with normal levels of GGT and higher levels of serum bile acid concentrations, while PFIC3 is associated with high gamma GGT and bile acid are mildly raised. Furthermore, bile acid synthesis disorders present low or absent serum bile acid in comparison to high levels in PFIC1/2.

Overall, patients with type 2 PFIC have more severe hepatobiliary disease with greater impairment of bile salt handling, increased prevalence of portal hypertension and hepatocellular carcinoma or cholangiocarcinoma in early life.⁶

Patients with PFIC2 have a variable prognosis depending on the type and severity of genetic defects. Treatment of PFIC2 consists of nutritional support (adequate calories intake, supplementation of fat-soluble vitamins and medium chain triglycerides) and medications to relieve pruritus. When medical treatment fails, partial biliary diversion or liver transplantation is indicated in patients with debilitating pruritus with poor quality of life and in patients with end-stage cirrhosis. Mutation targeted therapy, gene therapy or hepatocytes transplantation is being explored as future therapeutic options.⁶

Learning points.

• Atopic dermatitis (AD) is the most frequent cause of chronic pruritus in childhood.⁸ However, different underlying aetiology of pruritus and eczema lesions should be thought and researched when conventional therapeutic strategies fail.

• In a child with unresponsive AD, worsening pruritus and jaundice, a liver disorder should be suspected, and in some cases, it is caused by a genetic disorder. Liver function tests should be performed with particular importance like alanine aminotransferase, aspartate aminotransferase and gamma glutamyl transpeptidase (GGT). The differential diagnosis (obstructive, metabolic, infective, genetic and endocrinal causes) depends on the age of presentation and the GGT levels, which are very useful when cholestasis is suspected, because other common conditions responsible for neonatal cholestasis (biliary atresia, alagille syndrome, alpha 1 antitrypsin deficiency) are characterised by high GGT levels. Severe AD could lead to error and delay in the diagnosis of intrahepatic chronic cholestasis. In this case, severe pruritus, early onset of jaundice, poor growth and raised transaminase levels with normal GGT have raised the suspicion of a genetic cholestatic disorder.

• Only few cases of PFIC are reported in the literature, under no circumstances in association with AD.^{9 10} We concluded that this patient is a rare case of comorbidity between AD and type 2 progressive familial intrahepatic cholestasis (PFIC2). The homozygous mutation in the ABCB11 gene (c.2494C>G; p.Arg832Gly) associated with PFIC2 was due to paternal uniparental disomy of chromosome 2. In very rare patients with PFIC (<10%), only one mutated allele or no mutation is identified.¹¹ Here, we reported a rare autosomal recessive disease due to paternal uniparental disomy.