An Approach to a Neonate with Cholestatic Jaundice

There is a broad differential diagnosis for conjugated hyperbilirubinemia in the newborn period. If the patient appears

sick, the differential diagnosis includes sepsis, galactosemia,

and hypopituitarism. If the patient appears well, obstructive, infectious, and metabolic etiologies should be considered. 

Obstructive conditions include extrahepatic biliary

atresia, choledochal cyst, idiopathic neonatal hepatitis,

Alagille syndrome, gallstone, and cystic fibrosis. 

Biliary atresia must be evaluated with a liver ultrasound and liver biopsy quickly as long-term outcomes are better for infants who

undergo a Kasai procedure at age less than 60 days. 

Infants with biliary atresia typically are feeding and growing well and subsequently develop clay-colored stools as the bile flow

decreases. 

The abdominal ultrasound is also helpful in diagnosing other causes of cholestasis including a choledochal cyst or gallstones.

 Alagille syndrome is a genetic disorder with symptoms that include conjugated hyperbilirubinemia due to a lack of bile ducts, peripheral pulmonary stenosis, butterfly vertebrae, triangular facies, and eye abnormalities (posterior embryotoxon). Cystic fibrosis can also cause neonatal cholestasis.

Infectious causes of conjugated hyperbilirubinemia include

TORCHinfections, most commonly cytomegalovirus, urinary

tract infections, and sepsis due to Gram-negative bacteria.

Head ultrasound and eye examination are useful in identifying

TORCH infections.

 There are many metabolic causes of  conjugated hyperbilirubinemia including galactosemia and tyrosinemia, which are tested for on the newborn screen.

Urine reducing substances and succinylacetone are positive

in patients with galactosemia and tyrosinemia, respectively.

Hypothyroidism and panhypopituitarism can also lead to

cholestasis and can be diagnosed with appropriate hormonal

studies.

 Alpha-1-antitrypsin (A1AT) deficiency leads to accumulation of A1AT in the hepatocytes, which leads to abnormal bile secretion and cholestasis. Total parenteral nutrition and medication use are other important causes of cholestasis.

Medications that more commonly lead to conjugated hyperbilirubinemia include amoxicillinclavulanate, trimethoprimsulfamethoxazole, erythromycin, naproxen, and rifampin.

An infant with conjugated hyperbilirubinemia who otherwise

appears well should have a laboratory evaluation, which should include a basicmetabolic panel, AST, ALT,GGT, CBC with differential, ammonia, albumin, and coagulation studies.

 AST, ALT, and GGT levels are often elevated with

cholestasis due to liver cell or bile duct injury. 

The GGT level is normal or low in patients with bile acid synthesis defects and progressive familial intrahepatic cholestasis (PFIC). 

Prolonged prothrombin time, low albumin, and elevated ammonia

can be seen with cholestasis if there is advanced liver

injury.

 The newborn screening test results should be confirmed to be normal to rule out galactosemia and tyrosinemia.

Urine should be sent for urinalysis, urine culture and sensitivity,

and reducing substances to look for urinary tract infection

and galactosemia.

 An abdominal ultrasound should be performed early in the evaluation process to assess for biliary atresia, choledochal cyst, or other anatomic causes for cholestasis.

 While awaiting the test results, the parents should be counseled to have their infant evaluated if he develops fever, acholic stools, worsening jaundice, or easy bleeding.

Clinical case 2

An 11-day-old baby girl presents to her pediatrician with new

onset jaundice. She is a full term infant born via a spontaneous

vaginal delivery without any complications during the

pregnancy or delivery. Her total bilirubin at the time of

discharge from the full term nursery on day of life 2 was

6.5 mg/dL. The mother’s blood type is Oþ, and the infant’s

blood type is Bþ with the direct antibody test negative.

Maternal hepatitis B surface antigen is negative. She is breastfeeding every 2–3 hours with good weight gain.

She is afebrile without acholic stools, vomiting, irritability,

or bleeding. There is no family history of hyperbilirubinemia,

Alagille syndrome, or alpha-1-antirypsin deficiency.

Her vital signs are stable. Physical examination is normal

except for icterus. There is no dysmorphic facies, nystagmus,

heart murmur, or hepatosplenomegaly. Stool is yellow in

color.

Laboratory evaluation performed during the clinic visit shows a total bilirubin 8.5 mg/dL, conjugated bilirubin 3.5 mg/dL, aspartate aminotransferase 20 IU/L, alanine aminotransferase 46 IU/L, gamma-glutamyl transpeptidase (GGT) 288 IU/L, and alkaline phosphatase 163 IU/L.

 A complete blood count (CBC) shows white blood cell count

12.3 x 109/L, hemoglobin 17.7 g/dL, and platelets 248 x 109/L

with a differential of 26% segmented neutrophils, 58%

lymphocytes, 11% monocytes, and 5% eosinophils. Newborn

screening result is normal. The prothrombin time is 9.3 seconds.

 A liver ultrasound shows a normal appearing liver without intrahepatic or extrahepatic biliary dilatation.

Further evaluation included an alpha-1-antirypsin phenotype,

and toxoplasma IgM, which were normal. Urine was

negative for cytomegalovirus. TSH is normal.

Further evaluation reveals the cause of her conjugated

hyperbilirubinemia.

What do you think that investigation?

what was the diagnosis?


Answer


A catheterized urine sample was positive for nitrites and leukocyte esterase and showed 25–50 white blood cells and 5–50 bacteria/ high powered field.

 A urine culture subsequently grew >100,000 colonies/ mL of Escherichia coli. The infant was treated with 14 days of amoxicillin clavulanate. On day 5 of antibiotic treatment, the infant’s conjugated bilirubin decreased to 1.3 mg/dL, and two weeks after completing the course of antibiotics, the total bilirubin was 1.0 mg/dL and conjugated bilirubin was 0.4 mg/dL. As part of the evaluation for her urinary tract infection, she underwent a voiding
cystourethrogram and renal ultrasound that showed bilateral
grade 3 vesicoureteral reflux and bilateral Society for

Fetal Urology (SFU) grade 2 hydronephrosis, respectively


Lessons for the Clinician

• For neonates with jaundice, check a serum level of
conjugated bilirubin with the total bilirubin.

• A direct bilirubin may overestimate the conjugated
bilirubin.

• When evaluating a well-appearing infant with conjugated
hyperbilirubinemia, include a urinalysis and urine
culture.

• For full term, well-appearing infants<8 weeks of age with
jaundice, the risk of having a UTI is 5.5–7.5%. In these
cases, the hyperbilirubinemia will resolve with treatment

of the UTI.

clinical case

A 6-year-old girl presents with bilateral lower leg swelling, progressive fatigue,and ultimately, refusal to walk secondary to severe pain, which began a month ago.

She had a respiratory illness along with mouth sores one month prior to development of these symptoms. There is no history of fever, rash, travel or sick contacts. Family history is significant for leukemia, breast cancer, colon cancer, and osteoarthritis.

She is afebrile and has normal vital signs.Her lower extremity examination shows non-pitting edema over both ankles and knees. There is no tenderness or crepitus on palpation of her lower extremities. She moves her lower extremities spontaneously when lying in bed and has normal strength. She has pain with full extension of knees as well as with dorsiflexion of feet. There is no spinal tenderness, or limitation in range ofmotion of her back and hips. Sensations and deep tendon reflexes are intact bilaterally. She has significant apprehension when asked to walk, and bears weight briefly on her toes. In addition, she demonstrates marked emotional lability.

Laboratory results are as follows: WBC count 18.7K/mL (71% neutrophils, 0%

Bands), Hgb 10.4 g/dL, a platelet count 611 K/mL, and a normal peripheral smear.

Serum electrolytes, BUN, creatinine, liver enzymes, LDH, uric acid, creatinine kinase, aldolase and antineutrophil cytoplasmic antibodies (ANCA) are within normal limits. Her erythrocyte sedimentation rate is 127 mm/hr (0–10 mm/hr) and C-reactive protein is 5.8 mg/dL (0.0–0.9 mg/dL).MRI of the lower extremities reveals normal osseous structures with edema within the popliteal fossae and patchy muscular and fascial edema bilaterally . 

Evaluation for infectious processes, including bacterial cultures of blood and stool, respiratory viral panel, PPD, and serologic evaluation for Bartonella,

Parvovirus B19, Coccidiomycosis, EBV, CMV and mycoplasma

were negative. A bone scan was normal. An MRI of the brain and spine performed, after consultation with neurology because of behavioral changes, to rule out secondary CNS involvement, were normal.

She remains nonambulatory during first few days of hospitalization, until further evaluations reveal the diagnosis.

What do you think this investigation which was requested?

What is the diagnosis?

What is the treatment?


Because of markedly elevated inflammatory markers and inability to ambulate, our differential diagnosis included infectious, post-infectious, rheumatologic, and oncologic processes.

some of these have been excluded by the above mentioned investigation.

the test which reveal the diagnosis : ASO and DNAse B titers results came back at 447 IU/mL (0–99 IU/mL) and 340 (</ ¼ 170),

respectively. Thus a diagnosis of post streptococcal myositis
and fasciitis was made.

She was started on oral amoxicillin and non-steroidal antiinflammatory medications. In addition, physical therapy
was initiated, and within three days she showed marked
improvement. She was discharged home to complete a tenday
course of amoxicillin. At her one month follow up, she was back to her baseline activity level without pain, and her ASO titer and ESR had normalized.

Lessons for the Clinician:

• It is important to consider post-streptococcal related myalgia/myositis in the differential diagnosis of children presenting with diffuse muscle and fascial inflammation.

• Post-streptococcal related myalgia/myositis can have atypical
presentations, such as isolated myalgia and can mimic other serious diseases.

• Serum levels of muscle enzymes are normal in patients with post-streptococcal myositis.


Remember :

Post-streptococcal myositis has been reported in patients ranging is ages from 6 to 39 years and there has been a slight female predominance. All patients have presented with severe, debilitating myalgia, generally affecting the proximal muscles of the upper and lower extremities.


Patients generally have a neutrophil predominant leukocytosis,
mild anemia, thrombocytosis, elevated inflammatory markers, normal muscle enzymes and elevated ASO titer.

MRI would remain the modality of choice for establishing
diagnosis, and in our case indeed revealed inflammation
of both muscle and fascia without any bony involvement.

Imaging studies were not performed in the previously reported cases.

Treatment strategies have been variable, but generally included use of anti-inflammatory medications, antibiotics against group A Streptococcus and occasionally steroids for
refractory cases. 

Response to treatment is generally good, with most patients returning to baseline along with resolution of serologic evidence of inflammation.