Metabolic liver diseases (MLD) are frequently missed and hence underreported. They are responsible for significant pediatric mortality. A fair number of these patients have a potential for favorable outcome with prompt detection and management; thus increasing the awareness regarding such disorders is important. We highlight the profile of commonly encountered pediatric MLDs and available diagnostic and therapeutic facilities in the developing countries through this review.
3. is important in not only managing the index cases but also for
counseling in future pregnancies. A situation where more
than one child in the consanguineous family is affected
strongly suggests the diagnosis.1
We aim to highlight the type,
clinical, diagnostic and therapeutic profile of these disorders
existing in India and the rest of the developing world sharing
similar demographic and socioeconomic factors.
2. Methods
Articles published in last 40 years on pediatric metabolic liver
disease in India and other developing countries were studied.
Pubmed and Google scholar were used to identify common
and atypical clinical presentations, available diagnostic and
therapeutic modalities and the ultimate prognosis. Individual
diseases, names of the developing countries and pediatric
population were the key words used to search such condi-
tions. Primary inherited pediatric metabolic diseases pre-
dominantly involving liver were included where as other
congenital or acquired infective, inflammatory or neoplastic
liver diseases were excluded. Both authors were involved in
reviewing and selecting the reported cases as per the set se-
lection criteria. Of the 120 articles reviewed, 77 articles were
finally included in our review. In this review, isolated case
reports unless unique in some way have not been referenced
but studies reporting a case series or original articles have
been quoted.
In India, 25,000 newborns are born with MLDs annually.
These disorders account for 14% of childhood liver diseases in
India.2,3
They result in significant mortality and morbidity;
accounting for 8% cases of fulminant hepatic failure and 24%À
40 % cases of chronic liver disease.3e6
Although a quarter of
the children requiring liver transplantation have underlying
metabolic liver diseases; only a minority of such cases are
eventually referred for liver transplantation in our country
compared to developed nations.7
This is on account of poor
awareness, delayed diagnosis, delayed referral or unafford-
ability. There is even scarce reporting from other developing
nations; where metabolic liver diseases account for 10% of
childhood liver disorders.8e10
Despite the non-specific nature of disease presentation;
these conditions can be suspected based on age of onset;
clinical picture & biochemical tests (Table 1). Galactosemia,
organic acidemias, urea cycle defects & mitochondrial dis-
eases typically manifest soon after birth; hereditary fructose
intolerance & hereditary infantile tyrosinemia manifests
beyond 6 months of life; glycogen storage disorders & lyso-
somal storage disorders manifest beyond infancy whereas
Wilson disease typically presents in older children. MLDs can
be categorized according to their predominant type of hepatic
presentation which may give a clue to the specific etiology
(Table 2). Following is the brief account of commonly
encountered MLDs in the developing world.
2.1. Galactosemia
It results from genetic deficiencies in enzymes involved in
galactose metabolism namely galactose-1-uridyl transferase
(GALT) (commonest), galactokinase or uridyl
diphosphogalactose-4-epimerase (least common) resulting in
an inability to metabolize galactose. This condition accounts
for 6e20% of MLDs in Indian children.3,6
Exposure to milk
feeds following birth results in tissue accumulation of galac-
tose metabolites and organ dysfunction.1
Classic variant has
total enzyme deficiency or enzyme levels <10% of normal.
These cases present acutely with vomiting, lethargy and
diarrhea and over a period of time develop cataracts, hepatic
manifestations such as cholestasis and cirrhosis, renal
tubular dysfunction and ovarian failure. They are prone to
gram negative & fungal sepsis on account of altered neutro-
phil function. Duarte variant has mild enzymatic deficiency
and may present with neurodevelopmental delay, extrapyra-
midal signs and growth failure.11e13
This condition may
coexist with extrahepatic biliary atresia due to simultaneous
involvement of GALT and inversin genes.14
Ideally, this con-
dition should be detected during neonatal screening with
GALT assay. Non-adherence to routine neonatal screening
frequently results in delayed diagnosis. Positive urine Bene-
dict's test with presence of non glucose reducing sugar
(galactose) is a typical finding. Diagnosis is possible by esti-
mating galactose levels in blood and urine but can be affected
by dietary intake. Hence, quantitative enzyme estimation is a
preferred diagnostic test. Mutation testing and gene
sequencing is available for prenatal detection and prognosti-
cation. In a study on 55 children with GALT deficiency, N314D
(40%) was the commonest mutation and its combination with
Duarte 2 allelic variant was associated with better prognosis.11
In a South African study (17 cases; mean age at diagnosis 5.1
months); homozygous deletion of S135L was seen in black
children while Q188R deletion was common in white children
diagnosed with GALT deficiency.15
Treatment involves com-
plete elimination of galactose from diet including milk and
milk products and galactose containing medications. Soy
protein based (lactose free) formula should be used instead for
feeding along with calcium and vitamin supplementation to
maintain normal growth. Early and compliant therapy usually
reverses most of the disease manifestations.1
2.2. Hereditary fructose intolerance (HFI)
Deficiency of fructose-1-phosphate aldolase disrupts fructose
metabolism. It results in accumulation of fructose-1-
phosphate in the liver, kidneys and small intestine which
disrupts protein & ATP synthesis and results in organ
dysfunction.1
The condition is seen in 1 out of 20,000 live
births per year worldwide but has been infrequently reported
from India.2
Clinical presentation described usually at the
time of weaning includes intolerance to fruits with recurrent
vomiting, diarrhea, hypoglycemia, cataracts, increased blood
lactate, failure to thrive, renal tubular dysfunction, hepato-
megaly, portal hypertension and cirrhosis in adolescent
period.16
Diagnosis is suggested by presence of positive urine
non glucose reducing sugar (fructose). Fructose challenge test
is tedious. Urine osazone test demonstrates characteristic
needle shaped fructose crystals. Urine chromatography is
available and confirms the diagnosis. Mutation analysis is not
easily available in India. Although liver transplantation has
been reported in treating this condition, dietary elimination of
fructose is an effective therapy.1
a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e1 02
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Indian children e A review, Apollo Medicine (2015), http://dx.doi.org/10.1016/j.apme.2015.02.012
4. 2.3. Glycogen storage diseases (GSD)
These represent the enzymatic defects in glycogen metabolic
pathway predominantly affecting liver, muscle & heart with
an overall frequency of 1:20,000e1:25,000 live births.1
GSD
predominantly affecting liver are types 1, 3, 4, 6, 9 and 11. In
India, GSD account for 8e24% of pediatric MLDs.3,5,6
This
condition should be suspected in a child with hypoglycemia,
unexplained massive hepatomegaly, growth retardation and
characteristic doll like facies.17
Comorbidities include
Table 1 e Approach to metabolic liver disease.
(continued on next page)
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5. neutropenia, myopathy, hypertrophic cardiomyopathy, mac-
roglossia, lactic acidosis and gouty arthropathy.1
Piebaldism
has been associated with GSD1a.18
Fanconi-Bickel syndrome is a frequently reported GSD from
India. It represents mutations in GLUT2 or SLC2A2 gene
resulting in glycogen deposition in liver and renal tubules. The
diseases manifests in infancy with hypophosphatemic rickets
secondary to renal Fanconi syndrome, massive hepatomeg-
aly, hypoglycemia and neurodevelopmental delay.19,20
Defin-
itive diagnosis in suspected cases is possible on liver biopsy.
Presenceof diastasesensitive PAS positive glycogen staining
in hepatic tissue is helpful in making a group diagnosis of GSD.
Differentiation between different GSD subtypes is important
for optimum management and is achieved with enzyme assay,
histopathology and molecular analysis. Enzyme analysis in
leucocytes, liver, muscle or skin fibroblasts is available for
certain GSD subtypes. Mutation analysis and gene sequencing
isavailablefor common GSD1amutations: R83C(exon2), Q347X
(exon 5), G727T (exon5) and also permits prenatal diagnosis.21
A
simple clinical guide to identify the GSD sub type has been
presented below which is useful if enzyme analysis and mo-
lecular diagnosis is unavailable (Table 3).22
In a study on 10
cases with GSD (age range 0.5 ye6 y), GSD 1a was diagnosed in
20% cases on the basis of G6PC gene sequencing.23
However, in
a study on 17 children (mean age at onset 15 months; range
0e46 months) diagnosed with GSD on liver biopsy; none of the
cases tested positive for the common mutations.17
Careful pe-
riodic monitoring with hepatic ultrasound, alpha-fetoprotein
and carcinoembryonic antigen is important for early detec-
tion of hepatic adenomas & carcinomatous transformation in
patients with poor metabolic control. Periodic renal evaluation
for tubular dysfunction and glomerulosclerosis is important.
Medical management aims at avoiding hypoglycemia
especially in infants by providing sustained glucose supply.
This is usually given as uncooked corn starch which releases
glucose in a sustained fashion. Liver transplantation needs to
be done in progressive liver damage. Fanconi-Bickel syndrome
requires therapy with vitamin D, phosphate and alkali sup-
plementation to treat the tubular dysfunction.1
2.4. Hereditary infantile tyrosinemia (HT1)
Tyrosinemia type 1 results from deficiency of fumar-
ylacetoacetate hydrolase (FAH). This results in tissue accu-
mulation of the reactive metabolites such as
fumarylacetoacetate, maleylacetoacetate and their reduced
derivatives succinylacetoacetate and succinylacetone.1
Pro-
gressive liver disease coexisting with renal hypo-
phosphatemic rickets is a typical finding in infancy.24,25
There is an increased risk of hepatic carcinoma in these
cases. Diagnosis is suggested by presence of elevated serum
and urine succinylacetone levels. Plasma aminoacidogram
reveals elevated levels of tyrosine and methionine. FAH
enzyme assay in fibroblasts/lymphocytes though diagnostic,
is unavailable in our country. A high alpha fetoprotein level
even in the absence of a hepatocellular carcinoma may
suggest the diagnosis. Variant 1b is secondary to deficiency
of maleylacetoacetate isomerase. This variety is diagnosed
in absence of elevated d aminolevulinic acid and succinyla-
cetone but in presence of other biochemical abnormalities as
seen in type 1.26
FAH gene studies to identify common mu-
tations (G192T, IVS12p 5G > A, IVS6_1G > T and 10009G > A)
are available in India. Prenatal diagnosis is possible with
enzyme assay or mutation study on chorionic villus sam-
pling or elevated succinylacetone in amniotic fluid.24
Dietary
restriction of tyrosine and phenylalanine improves hepatic
Table 1 (continued)
a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e1 04
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Indian children e A review, Apollo Medicine (2015), http://dx.doi.org/10.1016/j.apme.2015.02.012
6. dysfunction but does not guarantee protection against ma-
lignancies. Liver transplantation used to be the only the
definitive therapy in the past. Nitrotrifluoromethylbenzene
(Nitisinone, NTBC) is a new drug which blocks the produc-
tion of reactive tyrosine metabolites and prevents hepatic
malignancy. However it is expensive and not easily
available.1
3. Gaucher disease (GD)
It is the commonest lysosomal storage disorder (LSD) ac-
counting for 6% of MLDs in India.6
Deficiency of b-gluco-
cerebrosidase secondary to GBA gene mutation results in
accumulation of glucocerebroside throughout the reticulo-
endothelial system. Common manifestations include
pancytopenia, splenohepatomegaly, portal hypertension,
developmental retardation and osteoaricular involvement
in the form of bone pains, avascular necrosis and charac-
teristic ‘Erlenmeyer flask bony deformity’.27
GD may mimic
clinical signs of hemolytic anemia.28
Type 1, the chronic non
neuronopathic type is the commonest variant.29
Worldwide,
this condition is common in people with Askenazi Jewish
ancestry.1
Mappila muslim community in Kerala has a
particularly high prevalence of this disorder.30
Types 2 & 3
have neurological affection of which type 2 is the most se-
vere type and usually fatal in infancy. Diagnosis is estab-
lished on the basis of deficient b-glucosidase activity in
peripheral blood leucocytes.30
Chitotriosidase levels are
significantly elevated in GD and Niemann Pick disease
compared to other LSD and signify macrophage activation
secondary to abnormal storage. This enzyme is used in
monitoring the response to treatment of GD.31
Demonstra-
tion of typical Gaucher cells in bone marrow or liver tissue
though suggestive; is not diagnostic and hence a bone
marrow study is not essential for diagnosis. L444P, N370S,
IVS2, D409H and 55Del account for 50% mutations in Indians
with GD. Of these L444P (c.1448T > C) is the commonest
mutation seen in almost 60% of cases which include Type 1
Table 2 e MLD according to predominant hepatic
presentation.
Hepatic presentation Possible etiologies
Encephalopathy/seizures/
recurrent vomiting
Organic acidemias, urea cycle
defects, fatty acid oxidation defects,
carbohydrate metabolism defects
Acute liver failure Tyrosinemia, galactosemia,
hereditary fructose intolerance,
neonatal hemochromatosis, urea
cycle defects, fatty acid oxidation
defects
Neonatal cholestasis
(without liver failure)
Nieman Pick type C, cystic fibrosis,
Citrin deficiency, alpha-1 antitrypsin
deficiency
Hepatomegaly Glycogen storage disorders;
hereditary fructose intolerance,
Wilson disease, fatty acid oxidation
defects
Hepatosplenomegaly Neiman Pick type C, Gaucher
disease, Wilson disease
Table3eApproachtoidentifyingGlycogenstoragedisorder(GSD)subtypesbasedonsimpleclinicalandbiochemicaltests.
GSDtypeFasting
hypoglycemia
Liver
enzymes
RenomegalyRenaltubular
affection
Serum
lactate
KetosisSpecificfeature
1
1a:VonGierke's
disease
þþþNþþ[ÀLiveradenomas,xanthomas,gout
Therapywithuncookedcornstarch
1a:Bleedingtendancy,glomerulosclerosis;prominentsteatosisonliverbiopsy,
1b:neutropenia,recurrentinfections,inflammatoryboweldisease
Rx:Livertransplantation
3
Cori'sdisease
þ[Àþ[þMyopathy(raisedcreatinephosphokinaselevels),
cardiomyopathy,cirrhosisaftermanyyears
Therapywithhighproteindiet,lessdependenceoncornstarchdiet
4
Andersen's
disease
À[ÀÀÀÀMildheartormuscleinvolvement,peripheralneuropathy(rare);
Cirrhosis&mortalityininfancyinprogressivetype.
Rx:Highproteindiet
6
Hers'disease
þ[þX-linkediscommonestvariety
Cardiomyopathy(rare)
9þ[ÀÀNþCardiomyopathy
11
Fanconi-Bickel
syndrome
þNþþ
Proximaltubular
dysfunction
NþModifiedketogenicdietandRxofrenaltubularacidosisneeded
a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e1 0 5
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Indian children e A review, Apollo Medicine (2015), http://dx.doi.org/10.1016/j.apme.2015.02.012
7. and type 3 GD.32,33
GBA gene sequencing and testing for
common Indian GD mutations is available in India. Prenatal
diagnosis is possible with fetal enzyme assay on amniotic
fluid. In a study involving 68 children (mean age at pre-
sentation 4.5 years); GD was the commonest LSD identified
in 15% cases.34
Prior to the introduction of enzyme
replacement therapy (ERT), the outcome remained univer-
sally poor and supportive treatment included splenectomy,
blood transfusions and reconstructive bone surgeries. Bone
marrow transplantation offers cure but is not devoid of
major complications. However ERT has shown promising
results even in the Indian population in significantly
improving the clinical & biochemical parameters without
any drug associated major adverse effects. Indications of
ERT include blood transfusion dependent anemia, symp-
tomatic thrombocytopenia, growth failure, progressive liver
disease and bone disease. Neurological affection is a
contraindication for ERT. The therapy regimen involves use
of recombinant macrophage-targeted glucocerebrosidase
which is administered as a slow intravenous infusion in
dose of 60 U/kg every two weeks initially and later titrated
as per the clinical response. In a multicenter study in India
involving 58 cases diagnosed with GD on enzyme assay,
Nagral et al described the demographic and clinical profile
of GD and highlighted the efficacy of ERT in improving the
quality of life in such cases. Significant improvement in
hematological parameters, growth, bone pains and regres-
sion in the size of organomegaly was observed while major
adverse effects were rarely encountered.35
4. Niemann Pick Disease (NPD)
NPD type A & B results from almost total or partial deficiency
of acid sphingomyelinase (ASM) respectively. The enzyme
defect is secondary to SMPD gene mutations resulting in
widespread lysosomal deposition of sphingomyelin in the
reticuloendothelial system and central nervous system.1
As
reported from India, NPD A is a fatal neuronopathic variant
with onset early in infancy presenting with pallor, cytopenias,
lymphadenopathy, progressive massive firm splenohepato-
megaly, chronic liver disease, psychomotor retardation,
extrapyramidal features in the form of tremors, rigidity, dys-
tonia and interstitial lung disease.36
There is a rapid progres-
sion resulting in death within first three years of life. NPD B is
the more common non neuronopathic variant with later onset
of similar symptoms and is usually compatible with life.
Retinal cherry red spot is present in a subset of cases. Clinical
suspicion is confirmed on bone marrow or liver biopsy with
demonstration of typical storage cells. The characteristic
histopathological findings also help to differentiate NPD from
GD. In NPD, light microscopy reveals large lipid laden foamy
vacuolated cells with eccentrically placed nuclei; electron
microscopy reveals engorged lysosomes with abnormal stor-
age material and myelin inclusions. This is responsible for the
typical ballooning of the neurons resulting in neurodegener-
ative symptoms.37
Sphingomyelinase enzyme assay is avail-
able in India & further confirms the diagnosis. While bone
marrow transplantation is possible, ERT is also now available
for treating NPD type B.1
5. Niemann Pick disease type C
This is a distinct condition resulting from inability to metab-
olize cholesterol resulting in systemic tissue deposition.
Clinical presentation includes prolonged neonatal jaundice,
hepatosplenomegaly and progressive neurodegenerative
course during childhood and adolescent period.38
Neurolog-
ical affection typically presents as scholastic decline, behav-
ioral problems, coarse facies, macular cherry red spot, ocular
movement problems including vertical supranuclear gaze
palsy and pyramidal and extrapyramidal motor dysfunction.
Neuroimaging reveals cerebellar vermian atrophy in addition
to symmetric leucoencephalopathy.1
Diagnosis is supported
by presence of foamy sea blue histiocytes in bone marrow and
confirmed by demonstration of increased cholesterol in
cultured fibroblasts and decreased cholesterol ester synthesis
in LDL incubated fibroblasts. Management is supportive and
includes cholesterol free diet and measures to decrease for-
mation of LDL cholesterol. Miglustat reduces glyco-
sphingolipid synthesis and thus improves neurological
symptoms.39
Although not easily available, it may be obtained
on compassionate basis.
5.1. Wilson disease (WD)
This is the commonest reported metabolic disorder worldwide
& accounts for 13% of pediatric liver diseases in India.3
It ac-
counts for 33%e53% of MLDs,3,6
13% of pediatric CLD5
and 13%
of pediatric liver disorders undergoing liver transplantation in
India.7
In Bangladesh, WD is responsible for 4% of all pediatric
liver disorders8
while in Pakistan, WD accounts for 16% of
pediatric CLD.9
Mutations in ATPase gene result in defective
copper excretion into bile which leads to systemic copper
deposition predominantly in liver and brain in addition to
other atypical manifestations. The age range of clinical pre-
sentation can be 3e55 years.40
Most Indian studies report a
delayed diagnosis. Liver disease in our subcontinent presents
either in the form of acute fulminant hepatitis with hemolysis
or as silent slowly progressive chronic liver disease and portal
hypertension. Neurological involvement presents in the form
of subtle neuropsychiatric symptoms such as change in
handwriting, altered behavior and cognitive decline or extra
pyramidal signs in the form of drooling, dystonia and ataxia.
Neurological involvement is more commonly reported from
Indian subcontinent as compared to hepatic involvement in
western countries. This may not necessarily mean that neu-
rowilson is more common than hepatic WD. A large study
from NIMHANS evaluated 307 children (mean age at presen-
tation 15.9 years) and found neurological involvement as the
commonest presentation in 70% cases followed by hepatic in
20% cases.41
This could represent a referral bias. However a
prospective study from Kolkata involving 34 children (mean
age 7.7 ± 2.13 years) detected hepatic involvement in 50% and
neurologic involvement in 20%.42
A study on 25 cases, re-
ported early presentation of hepatic involvement (mean age
6.8 years) compared to neurologic involvement (mean age
8years).43
Rare clinical manifestations reported from India
include cholelithiasis; Coombs negative hemolytic anemia;
gross hematuria, renal rickets secondary to renal tubular
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8. acidosis, hypokalemic limb & respiratory paralysis and pain-
ful arthropathy involving small and large joints.44e50
Systemic
copper deposition may also result in cardiomyopathy, auto-
nomic dysfunction and retinal dysfunction.51e53
Careful
family history and screening is important to identify the
affected members at presymptomatic stage. In a study from
eastern India involving 49 cases (mean age of onset 11.13
years), 50% cases were diagnosed at presymptomatic stage by
screening siblings of affected children.54
Serum cerulo-
plasmin, 24 h urine copper estimation (post penicillamine
challenge) and ophthalmological examination for presence of
KF rings is usually sufficient to make a laboratory diagnosis.
Low serum ceruloplasmin levels especially a value <5 mg/dL is
highly suggestive of WD. 24 h urine copper excretion >100 mg/
day are diagnostic of WD. Other inflammatory liver conditions
could also result in elevated urine copper levels. Urine levels
done post penicillamine challenge (500 mg D-penicillamine
given at start and at 12 h of 24 h urine collection) >1600 mg/day
are diagnostic in situations where suboptimal (<100 mg/day)
urine copper levels are present in presence of strong clinical
suspicion of WD. Free serum copper (serum Cu-{3x serum
ceruloplasmin}) is helpful in monitoring patients on chelation
therapy. Values between 5 and 15 microgram/dL suggest op-
timum copper chelation whereas values above and below this
range suggest under or over chelation respectively. Serum
copper has little role in diagnosis of WD. In younger patients
who do not have substantial extra hepatic systemic copper
deposition or do not excrete adequate copper to be detected by
urine or blood tests, hepatic copper estimation on liver biopsy
can be diagnostic. While values >50 mg/g dry wt are suggestive
of WD, value >250 mg/g dry wt confirm diagnosis. Adequacy of
liver tissue is to be ensured to avoid falsely low values of he-
patic copper resulting from inhomogeneous hepatic copper
deposition.40
About 16% of asymptomatic siblings of children
with WD are diagnosed with the help of haplotype analysis
and have better outcome.55
Mutation analysis from Indian
centres show that C813A is the commonest mutation out of 51
mutations detected in our country. The common Indian mu-
tations (Chandigarh group- T3305C, C2975A, 2977insA,
303insC; Kolkatta group e C813A; Vellore group- G3182Aand
C813A) are heterogeneous and differ from those reported
worldwide.41,56
There is 19%e54% mortality in cases present-
ing with acute liver failure (ALF). Encephalopathy, coagulop-
athy and raised serum bilirubin were the predictors of poor
outcome in such cases as reported in a study.57
Low copper
diet, copper chelation and zinc therapy help in managing this
disorder. D-penicillamine is the most commonly used chelator
in our patients, as it is cheap, effective and easily available.
Zinc is an effective and cheaper option for long term main-
tenance therapy and for pre symptomatic patients. A study
from NIMHANS demonstrated good outcome in 45 cases who
were shifted from penicillamine and zinc combination ther-
apy to zinc monotherapy due to non-affordability.58
Other
chelators such as trientine are expensive and not easily
available in India. Various objective evaluation scales
assessing hepatic, neuropsychiatric and osseomuscular
function have been described and may be useful in clinical
practice for disease monitoring. Aggarwal A, et al devised a
Global Assessment Scale (GAS) which is a two tier objective
scale evaluating hepatic, cognition, motor, osseomuscular
status and neurological function. They applied it in 30 cases
and found useful and reliable in monitoring the clinical
course.59
5.1.1. Organic acidemias (OA)
These are conditions associated with defective amino acid
catabolism secondary to enzymatic deficiency and urinary
excretion of non-amino organic acids in urine. About a quarter
cases present in neonatal period in the form of vomiting, poor
feeding, seizures, abnormal tone & encephalopathy. About
55% cases develop intellectual retardation.60
They may pre-
sent with sepsis like picture due to associated neutropenia
and thrombocytopenia. Laboratory findings include severe
high anion gap metabolic acidosis, hyperammonemia,
ketosis, hypoglycemia with deranged liver function tests.
Macrocephaly, cortical atrophy and cerebral edema are the
typical neuroimaging features. Urinary organic acid and
plasma amino acid profile on high performance liquid chro-
matography (HPLC) during symptomatic period can identify
abnormal metabolites. Propionic academia (19e35%) and
methylmalonic aciduria (9e33%) are the most commonly re-
ported OAs from India, followed by maple syrup urine disease
and isovaleric aciduria.60,61
Correction of biochemical distur-
bances during the acute phase by providing adequate hydra-
tion, temporary discontinuation of protein in diet, glucose and
multivitamin supplementation is the mainstay of supportive
therapy. Liver transplantation has been successful in few
cases.1
5.1.2. Urea cycle disorders
These are secondary to enzymatic defects in ammonia
detoxification pathway. Most cases present in neonatal period
with vomiting, poor appetite, aversion to proteins and may
suffer permanent neurological damage.1
The age of presen-
tation is inversely proportional to the severity of enzyme
deficiency. A high plasma ammonia in presence of normal
blood glucose suggest a urea cycle defect. Of the various de-
fects, classical citrullinemia is the commonest entity reported
from India. Diagnosis is based on demonstration of high
citrulline levels on tandem mass spectroscopy (TMS) and
urine chromatography. Definitive diagnosis is based on
enzyme analysis on tissue samples which is not available in
India. In a study describing clinical and mutational profile of
four children with urea cycle defects; three cases with cit-
rullinemia had G390R, R157H, R265C mutations while the
fourth case diagnosed with ornithine transcarbomylase defi-
ciency had c.988_c.989delAG mutation in ASSI gene.62
Prenatal
diagnosis has been possible with the help of mutation testing.
Prompt diagnosis, avoiding protein intake, supplementing
non protein calories and other therapy like arginine, sodium
benzoate, sodium phenyl acetate, carnitine and multivitamin
supplementation is helpful. Occasionally, dialysis may be
needed to clear off the excess ammonia from body.63
Liver
transplantation is the definitive option in recalcitrant cases.1
5.1.3. Citrin deficiency (NICCD) & citrullinemia type 2 (CTLN
2)
Mutations in SLC25A13 gene results in deficiency of citrin; a
mitochondrial aspartate glutamate carrier protein involved in
malate-aspartate shuttle and urea cycle. It is an important
a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e1 0 7
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9. etiology of neonatal cholestasis (neonatal intrahepatic chole-
stasis caused by citrin deficiency; NICCD) & is responsible for
almost 13e33% cases in Asian studies though not reported
from India.64
It also results in hypoproteinemia, hypoglycemia
and hypergalactosemia. Hyperammonemia is not seen in
NICCD unlike the adult form (CTLN2). Most cases of neonatal
cholestasis resolve spontaneously by the first birthday, but
may occasionally develop chronic liver disease. Plasma amino
acid profile may transiently show hypercitrullinemia.65
Mo-
lecular testing is considered diagnostic of this condition.
851del14 (GTAT del) is the commonest mutation in Asians.66
Mutation studies are currently unavailable in our country.
Liver histopathology typically demonstrates hepatic steatosis,
necrosis, cholestasis and fibrosis eventually progressing to
cirrhosis in few cases.67
Management involves supportive care
of neonatal cholestasis along with supplementation with
lactose free formula to manage secondary galactosemia.65
5.2. Progressive familial intrahepatic cholestasis (PFIC)
This entity represents defect in transport of bile acids leading
to early onset cholestasis with intractable pruritus & cirrhosis.
Liver histology typically demonstrates giant cells, cholestasis,
bile duct paucity, necrosis and fibrosis. In PFIC types 1 and 2,
GGT is low or normal and raised in PFIC type 3.1
Gene muta-
tion studies are available but expensive. Immunostaining may
serve as a cheaper screening method to identify the different
subtypes. Treatment involves choleretic agents to provide
symptomatic relief and improve cholestasis. Non cirrhotic
cases benefit from biliary diversion procedures while liver
transplantation is required in presence of established
cirrhosis as reported in Indian studies, although type 1 disease
with extra hepatic manifestations may not benefit.68
5.3. Primary hyperoxaluria (PH1)
Deficiency of hepatic alanine glyoxylate aminiotransferase
(AGT) leads to PH1. Oxalate overproduction with neph-
rocalcinosis, calcium oxalate urolithiasis, early onset chronic
renal failure and secondary systemic oxalosis is the usual
presentation in Indian children.69
Diagnosis is established by
demonstrating birefringent oxalate crystals in renal tissue on
polarized microscopy, estimation of urinary organic acids or
urinary oxalate excretion. Liver biopsy for demonstrating
deficient AGT activity although considered gold standard, is
not easily available.1
Whole gene sequencing of AGXT gene is
available in India and is helpful for diagnosis, prognostication
and prenatal diagnosis. C.302T >C is the commonest mutation
reported from India.70
Pyridoxine supplementation is helpful
in 60% cases. Early combined liver and kidney transplantation
is curative.1
5.4. Hepatic porphyrias
Abnormalities in heme biosynthesis lead to accumulation of
heme precursors in liver and erythroid bone marrow resulting
in multisystem manifestations. Acute intermittent porphyria
is secondary to deficient porphobilinogen deaminase activity.
It is the most severe and commonest type seen in our coun-
try.71
This condition has been reported to be particularly
common in Kumhar community from Rajasthan.72
It is more
often seen after puberty and in females during the menstrual
cycle. Common presentation includes abdominal pain, en-
cephalopathy, cortical blindness and peripheral motor poly-
neuropathy with autonomic dysfunction and respiratory
paralysis.73
Presence of porphyrinogen in urine is diagnostic.
Management comprises of critical care support including
intravenous fluids, heme preparations (which are not avail-
able in India) and seizure control. Certain drugs known to
precipitate such attacks should be avoided.1
Neonatal Hemochromatosis is an uncommon condition
which begins in utero secondary to maternal alloimmuniza-
tion to a fetal antigen. It presents as fatal neonatal hepatic
necrosis with liver failure with extra hepatic iron deposition.74
MRI spectroscopy and buccal mucosal biopsy can detect the
abnormal iron deposition. Desferrioxamine, N-acetylcysteine,
Vit E, selenium and IVIG have been tried in managing such
cases. Liver transplantation is considered curative.1
5.5. Alpha-1 antitrypsin (AAT) deficiency
This results from deficiency of protease inhibitor alpha-1
antitrypsin leading to abnormal glycoprotein deposition in
hepatic tissue causing damage. Although considered to be
common cause of chronic liver diseases and chronic
obstructive pulmonary disease in Caucasians, AAT is rare in
Indian subcontinent. Hepatic involvement is in the form of
neonatal cholestasis which may progress to acute liver failure
or cirrhosis.75
Diagnosis is suggested in presence of low serum
AAT levels, PAS positive diastase resistant granules on liver
histology and absent or faint alpha 1 globulin band on serum
electrophoresis. However, these are initial screening tests
which lack specificity and are associated with high false
positivity as also reported by an Indian study.76
Phenotype
analysis (PiZZ) by isoelectric focusing is cumbersome & does
not pick up null alleles. Mutation analysis is considered gold
standard and is available in India. Liver transplantation helps
to cure the liver disease and prevents future pulmonary
complications.1
Certain conditions such as fatty acid oxidation defects and
congenital disorders of glycosylation (CDG) have been rarely
reported from India.60,77
6. Centres for testing for metabolic liver
diseases in India
Sandor Proteomics Pvt Ltd, Hyderabad; Center of Medical Ge-
netics, Sir Ganga Ram Hospital; New Delhi; Neogen Labs,
Bangalore; Center for Human genetics, Bangalore; Institute of
Human Genetics, Ahmedabad; Nirman, Navi Mumbai.
7. Conclusions
Although increasing number of metabolic diseases are being
reported from our subcontinent, there is still gross under-
diagnoses and underreporting. This is on account of lack of
awareness and lack of diagnostic facilities. The clinical &
mutational profile of these conditions in developing countries
a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) 1 e1 08
Please cite this article in press as: Sathe KP, Nagral A, Metabolic liver disease in developing world with special reference to
Indian children e A review, Apollo Medicine (2015), http://dx.doi.org/10.1016/j.apme.2015.02.012
10. also seems to differ from the developed world. Hence it is
important to be aware of locally encountered conditions to get a
true estimate of the disease burden. Wilson disease followed by
galactosemia, gaucher disease, glycogen storage disorder and
organic acidemias are the common metabolic conditions re-
ported from India. Certain conditions such as AAT deficiency is
common in Western world but are rare in our subcontinent.
There isa need to make diagnostic facilities more accessible and
affordable togeta truepictureofthe spectrumandprevalenceof
the metabolic liver diseases in India. Setting up of disease spe-
cific registries would be an important step in this direction.
Conflicts of interest
All authors have none to declare.
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Indian children e A review, Apollo Medicine (2015), http://dx.doi.org/10.1016/j.apme.2015.02.012