Unraveling the Mysteries – Decompensated liver disease in a two month old ba.

Dr Sree Lekshmy.S, Dr.C.Jayakumar, Dr.Bhanu Vikraman Pillai, Dr.Anupa, (Paed Gastro)Dr.Sheela Namboothiri. (Paedgenetics)

Two month old male ba, first child of non consangenous parentage presented with history pale coloured stools and high coloured urine since 1 week of age. 
At the time of admission ba was irritable, had stable vitals. 
Clinically child had pallor and jaundice. Systemic examination revealed distended abdomen with dilated veins, umbilical hernia, firm liver was palpable 3cm below right costal margin and spleen palpable 3cm below left costal margin. 
Labs 
TC- 21.10Ku/ml, Hb-7.6g/dl
TSB-23.10mg/dl, DSB-19.24mg/dl, 
SGOT/SGPT- 1138/237IU
INR of 1.7with
Ammonia  147

Differentials considered :
Biliary atresia
Sepsis
Neonatal hepatitis 
Alpha-1 anti trypsin deficiency
Metabolic disorders like galactosemia, Tyrosenemia. 
Ba was started on IV Piperacillin- Tazobactam, IV  N acetyl cysteine ,Inj Vitamin K and other supportive measures. 
USG Abdomen  hepatomegaly with multiple variable sized hypoechoic lesions  scattered in both lobes, largest in segment IV measuring 8 x7 mm. Suspicion of disseminated ?infective etiology. 
CT Abdomen showed hypodense lesion measuring 3mm noted in segment VII liver. USG detected multiple hypoechoic areas not visualised in CT .
Blood and Urine CS were sterile. 
TORCH IgM was positive for CMV and hence CMV PCR blood quantification was done 
Titre 6811.5 copies -very high (Normal less than 60) 
Ba was also started on oral Valganciclovir.
Ba was given serial FFP for 3 days and coagulopathy was corrected 
Following this  USG guided Liver biopsy was done  and sent for HPE and special stains. Liver biopsy showed features of Neonatal giant cell hepatitis with fibrosis and liver tissue showing distorted architecture, areas of hyalinisation and widened portal tracts. 
The widened tracts show ductular proliferation, damaged native ducts, prominent arterial profiles, mild mixed inflammation composed of lymphocytes, eosinophils, neutrophils and occasional plasma cells and the distorted parenchyma shows prominent giant cell transformation of hepatocytes, canalicular cholestasis with cholestatic rosette formation, focal congested sinusoids and two tonedhepatocytes. 
After Genetics consultation total galactose TMS-GCMS and Whole Exome Sequencing was done 
Lymphocyte subset analysis and NBT/DHR which were normal. Opthal evaluation did not show findings of intrauterine infections, storage disorders or posterior embryotoxon. 
Serial monitoring of LFTs showed an increasing trend along with progressive ascites, hence ba was started on diuretics – Furosemide and Spironolactone. TMS-GCMS was normal. 
Galactose levels, 
total carnitine levels, acyl carnitine levels were normal. 
Urine succinyl acetone to rule out tyrosinemia was negative. 
Repeat CMV PCR was negative. 
WES showed homozygous mutation in NPC1 gene (Niemann Pick type C1)c.1130C>T.
After the whole exome sequencing results , it was decided not to proceed with Liver Transplant and wait for enzyme replacement therapy. Ba was being managed medically with diuretics and mega dose vitamins.

Discussion:
Neimann-Pick disease (NPD) is an autosomal recessive, lysosomal storage disease caused Acid Sphingomyelin deficiency(ASMD), which catalyses the hydrolysis of sphingomyelin(SM) to ceramide and phosphocholine. 
As a result the SM and its precursor lipids accumulate in lysosomes, mainly the macrophages. These lipid laden macrophages deposit in the liver, spleen, lungs and the brain causing hepatosplenomegaly, cytopenias, lung disease and neurological symptoms.  
There are 3 types. Type A,B and C .

Etiology
NPD types A and B are caused missense mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. 
NPD type C is caused mutations in NPC1 (located on chromosome 18) and NPC2 (located on chromosome 14) genes. 

Incidence is 1 in 250,000 individuals in Type A&B. NPD type C affects 1 in 150,000 persons.
Histology shows lipid-laden macrophages in the marrow, also called foam-cells. Numerous small vacuoles of relatively uniform size are created, which give the cytoplasm a foamy appearance. Electron microscopy shows electron-opaque, concentrically laminated inclusions within the macrophage cytoplasm.

Clinical features include jaundice, Hepatomegaly, Splenomegaly, Interstitial lung disease, Recurrent lunginfections, Thrombocytopenia, Hypercholesterolemia, Ataxia, Dystonia, Dysphagia, Dysphonia, Developmental delay and/or regression, Mental retardation.
Evaluation is measuring the activity of (Acid Sphingomyelin) ASM in leukocytes for Type A&B. For type C, a skin biopsy is taken and stained with a special stain, ‘filipin,’ to measure the enzyme activity. 
Treatment : type A and B Niemann-Pick disease (NPD), there is no cure. Supportive care is the mainstay of treatment. For type C, physical therapy is provided for neurological symptoms. Pain is managed with analgesics. 
Miglustat is a glucosylceramide synthase inhibitor and helps in Niemann-Pick disease and Gaucher disease decreasing glucocerebroside production.
Complications include fulminant hepatic failure, respiratory insufficiency, coronary artery and valvular heart diseases and seizures.
Prognosis : Type A is almost always fatal, and affected children are unlikely to live beyond 4 years of age. Type B have a slightly better prognosis than type A and may live till late childhood or early adulthood. Type C, prognosis depends on the time of the initial presentation. If it affects in infancy, the chances are very poor for survival beyond 5 years of age. If it affects after 5 years, then Type C patients may live to the age of 20 years.