Essential Revision Notes in Paediatrics for MRCPCH-Part 1

-Functional platelet abnormalities classification

Congenital

Defects of platelet membrane

@ Clanzmann thrombasthenia
rare, autosomal recessive, failure to aggregate, normal platelet count and
morphology

@ Bernard-Soulier syndrome

rare, autosomal recessive, failure of adhesion, no receptor to bind to vWF, giant

platelets, moderate platelet count reduction

Deficiency of storage granules

@ Wiskott-Aldrich syndrome
@ Chediak-Higashi syndrome

Defects of thromboxane deficiency

@ e.g. thromboxane synthetase deficiency

- cyclo-oxygenase deficiency

Acquired
@ Renal failure
@ Liver failure

Myeloproliferative disorders
Acute leukaemia, especially myeloid
@ Chronic hypoglycaemia
@ Drugs
@ Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), penicillin, cephalosporin,
sodium valproate

Investigations

A prolonged bleeding time and normal or moderately reduced platelet count are the
characteristic hallmarks of a congenitallhereditary platelet disorder (or von Willebrand
disease)
@ Platelet size followed by tests of aggregation and secretion in response to ADP, collagen,
arachidonate and ristocetin will be necessary

Esser-rtialRevision Notes in R7ediatrics tbr the MRCPCH 2nd Edition

9. BLOOD FILM

9.1 Approach to a blood film at MRCPCH level

I s the pathology in the red or white blood cell?

This is the first and most vital question you need to ask yourself when presented with a
blood film to interpret. Apart from the accompanying history being important in helping
you to answer this question, the other clue will be the number of white cells seen. If there is
an abundance of white cells the likelihood that the pathology will be in the white cells is
very high, and I will go as far as to say that acute lymphoblastic leukaemia will be top of

your differential diagnosis. If only an occasional white cell is seen then red cell pathology is
likely. Platelet pathology will be unlikely at MRCPCH level - the only real possibility is

one of giant platelets (same size as a red cell, or bigger) in Bernard-Soulier syndrome.

Red cell pathology?

Once you have decided on red cell pathology then look at the following parameters.

Shape

Sickle-shaped cells, as in sickle-cell disease
Fragments of red cells (e.g. helmet cells, etc.) indicative of microangiopathic haemolysis
such as in the haemolytic-uraemic syndrome
All different shapes, i.e. poikilocytosis as in thalassaemia, sickle-cell, iron deficiency
anaemia

Size
Small cells or microcytosis in iron deficiency anaemia
Large cells or macrocytosis in vitamin BIZ.andlor folatedeficient'anaemia
Different sizes: anisocytosis (haemoglobinopathies, anaemias)

Amount of central pallor in red cell
No central pallor: spherocytosis (hereditary spherocytosis, haemolytic conditions, burns
for example)
Large central pallor: hypochromic anaemia
'Halo' central pallor: target cells (haemoglobinopathies, hyposplenism)

Red cell inclusions

Malaria: most commonly Plasmodium falciparum, seen as a 'signet-ring' inclusion
Howell-Jolly bodies: remnants of nuclear fragments, seen in hyposplenism
Heinz bodies: denatured haemoglobin, resulting from oxidant stress (e.g. G6PD) or
haernolysis; can only be seen with a special stain, so if normal staining was used then it
is most likely a Howell-Jolly body

Basophilic stippling: multiple small inclusions in a red cell -e.g. lead poisoning

Haematology and Oncology

White cell pathology?

The abundance of white cells is most likely to be leukaemia at the MRCPCH level. A
lymphoblast cell is recognized by its size (large), with a large nucleus taking up nearly the
entire cell with only a rim of cytoplasm remaining (in contrast, a mature neutrophil has a
multilobed small nucleus). The morphological differentiation between acute lymphoblastic
leukaemia (ALL) and acute myeloid leukaemia (AML) is not realistic at this level, but
remember the relative incidence of each, 4 : 1, respectively.

COAGULATION

A representation of the coagulation cascades is shown below. It consists of an extrinsic
pathway (tissue thromboplastin is the initiator) and the intrinsic pathway (what happens in
the blood when it clots away from the body). These two pathways share a common final
pathway resulting in the production of a fibrin clot.

1

EXTRINSIC SYSTEM INTRINSIC SYSTEM

Tissue Factor XI1
thromboplastin Factor XI
Factor IX
Factor VII Factor Vlll
Platelet phospholipid
Calcium

1 1FactorX
Factor V
Calcium

Factor I1 (Prothrombin)
rThr-in-l
-Fibrinogen
Fibrin

(APTT)
(PT)

Representation of the coagulation cascades

41 1

Essentic~Rl evision Notes in P'ediatrics for the MRCPCH 2nd Edition

The system can be divided into boxes, each box representing one of the following three
basic screening tests of coagulation:

Prothrombin time (PT) measures the extrinsic system and common pathway
Activated partial thromboplastin time (APTT) measures the intrinsic system and
common pathway
Thrombin time (TT) measures the final part of the common pathway, it is prolonged by
the lack of fibrinogen and by inhibitors of this conversion, e,g. heparin and fibrin
degradation products

10.1 Natural anticoagulants

It is important that thrombin is limited to the site of injury. This is achieved by circulating
inhibitors of coagulation:

Antithrombin Ill-the most potent inhibitor, heparin potentiates its effect markedly

Protein C inhibits factors Va and Vllla and promotes fibrinolysis
The action of protein C is enhanced by protein S

10.2 Coagulation disorders

Haemophilia A (factor VIII deficiencyor absence)

Levels of factor Vlll in carriers are variable because of random inactivation of the X
chromosome (lyonization). As a result, DNA probes are now recommended to detect
carrier status
Prolonged APTT and factor VIll clotting assay reduced
Bleeding time and prothrombin times are normal
Vasopressin (DDAVP) may be useful in releasing endogenous factor.~llflrom its stores in
mild haemophilia. Tranexamic acid, by inhibiting fibrinolysis, may.be useful

Haemophilia B (factorIXdeficiencyor absence),Christmasdisease

Exactly the same as above, except factor IX is involved rather than factor Vlll
Incidence is one-fifth that of haemophilia A

von Willebranddisease

von Willebrand disease (vWD) is a more complicated entity compared to haemophilia A or

B and is generally poorly described - hence it is often overlooked in clinical practice. It

therefore deserves an in-depth explanation.
von Willebrand factor (vWF), is an adhesive glycoprotein encoded by a gene on chromo-
some 12. It is produced by endothelial cells and by platelets. vWF has two main functions:

To stabilize and protect circulating factor Vlll from proteolytic enzymes
To mediate platelet adhesion

Haernatology and Oncology

vWD will therefore result when the synthesis of vWF is reduced or when abnormal vWF is
produced.

The clinical presentation of vWD will include the following:

Mucous membrane bleeding
Excess bleeding following surgicalldental procedures
Easy bruising

Three types (at least) have been described

Type 1 vWD

Most common, accounts for at least 7O0/0 of vWD

Due to a partial deficiency of vWF
Autosomal dominant

Type 2 vWD
Due to abnormal function of vWF

Type 3 vWD

Due to the complete absence of vWF

Can often be mistaken for haemophilia A because factor Vlll levels will be low as there is
no vWF to protect factor Vlll from proteolysis. Laboratory results are important in distin-
guishing the types of vWD and in the differentiation from haemophilia. Ifl vWD type 1 the
following results will be expected:

Platelet count N
Bleeding time
Factor Vlll N/f
vWF
Ristocetin cofactor activity 1
1
1

Ristocetin, an antibiotic, is now confined to laboratory-only use after it was documented to
cause significant thrombocytopenia. Ristocetin, when added to a patient's plasma, will bind
vWF and platelets together causing platelet aggregation (hence, the clinical thrombocyto-
penia). In the absence of vWF, no platelet aggregation will be seen (vWF type 3). In the
presence of decreased vWF, diminished aggregation will ensue (vWD type 1). Hence, when
faced with the clinical picture of haemophilia A (bruising, normal platelet count, slightly
increased bleeding time and a decreased factor VIII), the ristocetin cofactor test will be able
to differentiate between vWD (decreased) and haemophilia A (normal).

Haemorrhagicdisease of the newborn

Vitamin K-dependent factors are low at birth and fall further in breast-fed infants in the
first few days of life

Essential Revision Notes in Paediatrics t i ~trhe MRCPCH 2nd Edition

Other factors associated with this deficiency include:
Liver-cell immaturity
Lack of gut bacterial synthesis of the vitamin K
Low quantities in breast milk

Haemorrhage is usually between day 2 and day 4 of life
PT and APTT are both abnormal, while the platelet count and fibrinogen levels are
normal. Fibrin degradation products will not be detected
Treatment is with vitamin K, either administered intramuscularly at birth or orally on day
1, followed by interval dosing thereafter

Prophylactic vitamin K remains controversial -see further reading

1 MALIGNANT PATHOLOGY

There are 1,200 new cases of malignancy diagnosed each year in the UK in children

under 15 years of age (an incidence of 1 in 600 children < 15 years)

The relative incidence rates for the different tumour types is illustrated below
Leukaemia, together with lymphoma, accounts for nearly 5O0/0 of all cases
Brain and spinal cord tumours are the most commonly occurring solid tumours
Overall, childhood cancer is about one-third more common in boys than girls

35%
30% Relative incidencerates of childhood cancers

25% Key
20%
15% Leuk la+emia
10% Lymph lymphoma.
BmidS braidspinalcord
5% S0ftti.s softtissue
Wtlms Wtlms' tumwr
Nwmb neuroblnstoma
Rstlno raUnoMastoma

G m C gemcell tumour
Epith epithdbmas

0%

Leuk Lymph BralnlS SoR Us Wtlms Nwrob h e Retino Germ C Epith Other

Environmentalfactorspredisposing to cancer

Ultraviolet radiation -skin cancer, particularly malignant melanoma

Ionizing radiation
Preconceptual paternal exposure -remains controversial

In vitro exposure - increased incidence of leukaemia

Postnatal exposure -leukaemia

Electromagnetic fields - remains controversial

Haernatology and Oncology

Syndromes/conditions predisposingto cancer

Syndrome Cancer

Down Acute leukaemia
20 times more susceptible than population
Neurofibromatosis type 1

I

1 1 . Leukaemia

The leukaemias can be divided into acute and chronic leukaemia. Chronic leukaemia

accounts for less than 5% of all leukaemias in childhood - all of these cases would be

chronic myeloid leukaemia (CML) as chronic lymphoblastic leukaemia does not exist in
childhood.

Esserltial Rcvisiol? Notes in Pc~edtixcic~s tbr the MRCPCH 2nd Edition

LEUKAEMIA CHRONIC (5%)

A-ACUTE (95%)

ALL (80%) AML (20%)

In acute leukaemia, a differentiating white cell undergoes a structural and/or numerical
change in its genetic make-up, causing a failure of further differentiation and
dysregulated proliferation and clonal expansion
Aetiology remains unknown, although associations or risk factors have been identified

Chromosomal breakage or defective DNA repair mechanisms (e.g. Fanconi anaemia,
ataxia telangiectasia)

Chemotherapy -second tumour effect

Immunodeficiency syndrome, for example Wiskott-Aldrich
Trisomy 21
Identical twin, especially if twin contracted leukaemia in infancy
Ionizing radiation
Clinical presentation is related to bone marrow failure and possibly to extramedullary
involvement

Acute lymphoblasticleukaemia

Acute lymphoblastic leukaemia (ALL) is divided into B-cell or T-cell -ALL depending on
which cell line (determined by immunophenotyping) is affected. .The majority of cases
(>80%) originate from the B-cell line with early pre-B, or common ALL-(cfiL), being the
commonest. About 15% are T-cell ALL with 2% demonstrating mixed lineage. CALLhas the
most favourable prognosis out of all the immunophenotypes.

Poor prognostic signs in ALL include:

Presenting white cell count (WCC) greater than 50 x 109/1

Outside the age range 2-9 years
Males do less well than females
Chromosomal abnormalities/translocations: rearrangement of the Mixed Lineage
Leukaemia (MLL) gene (11q23), e.g. t(4:ll) purports a poor prognosis, while t(9:22)
involving the Philadelphia chromosome carries a dismal prognosis
Normal diploid number of chromosomes in blast cell (hyperdiploidy carries a more
favourable prognosis)
Afro-Caribbean ethnicity
CNS disease

The poor risk or prognostic factors above are now used to tailor treatment, i.e. a child with
a high WCC will receive more intensive treatment than if the WCC had been normal.
Treatment is in the form of intensification blocks with ongoing maintenance therapy in

416

Hnematology and Oncology

between. Cytotoxic/chemotherapy agents used in the treatment of leukaemia include the
following: corticosteroids (prednisone and/or dexamethasone, vincristine, asparaginase,
daunorubicin/doxorubicin, cytarabine, cyclophosphamide, methotrexate, mercaptopurine,
CNS-directed treatment is a vital component of treatment because lymphoblasts can be
protected from standard chemotherapy by being on the 'other-side' of the blood-brain
barrier. In standard-risk children this will comprise intrathecal chemotherapy at regular
intervals; but for higher risk children, high-dose intravenous methotrexate (at a sufficient
dose to cross the blood-brain barrier) or craniospinal radiotherapy may be required. The
latter is the most effective in sterilizing the CNS of lymphoblasts, but it has a high price to
pay in that the neurocognitive side-effects can be profound. Treatment is over 2.5-3 years.
Bone marrow transplantation is generally reserved for specific patients with relapsing ALL or
with extremely poor prognosis ALL. The 5-year survival rate for standard-risk ALL is now
approximately 80%.

Acute myeloid leukaemia (AML)

* Is divided into seven subtypes depending on morphology (FAB - French, American,

British classification) and immunophenotypingcharacteristics - MI to M7

Chromosomal abnormalities occur in at least 80% of cases, with translocations the most
common
Treatment is with a more intensive, but shorter (6 months) chemotherapy regimen than
that used for ALL
Bone marrow transplantation plays a much more prominent role in the treatment of
AML although its use remains controversial in some subsets of patients because the
increased complete remission rates with this modality need to be weighed up against
the increased mortality of the transplantation procedure
Five-year survival figures are now in excess of 50%

11.2 Lymphoma

Two types of lymphoma are recognized: non-Hodgkin lymphoma (NHL) and Hodgkin
lymphoma (HL). In NHL the originating cell is either a B or T lymphocyte or an immature
form thereof, while in HL the originating cell is a B-lineage lymphoid cell. Histologically,
the presence of the Reed-Sternberg cell remains pathognomonic of HL.

Non-Hodgkinlymphoma

NHL is the term adopted to describe a heterogeneous group of malignant proliferations
of lymphoid tissue
The classification of NHL is complicated, and controversial. A practical way of
classifying NHL is to divide the entities into immature forms (T- or B-cell acute

lymphoblastic lymphoma), mature form (e.g. Burkitt lymphoma - a mature B-cell NHL)

and large cell lymphomas (e.g. anaplastic large cell lymphoma, diffuse 6-cell large cell
lymphoma, peripheral T-cell lymphoma)

The acute lymphoblastic lymphoma form of NHL is derived from the same T- and 8-

lineage lymphoid cells as ALL, but an important difference exists between these two

Essential Revision Notes it? Paedi,~tric-stor the k1KCPCH 2nd Edition

entities. In ALL, 80% of cases are pre-B-cell-derived; while 20% are T-cell-derived. In
NHL this is reversed, with T-cell tumours predominating

The following sites are commonly affected, in descending order of frequency:

Abdomen - usually with 6-cell disease
Mediastinum-typically T cell in origin
Head and neck - no specific cell

Chemotherapy is the mainstay of treatment because NHL i s a systemic disease, despite the
apparent local sites of disease

Hodgkin lymphoma (HL)

Painless cervical lymphadenopathy is the most frequent presenting symptom
The EBV-related causal hypothesis remains unproven
An excision biopsy of the entire lymph node, not just a biopsy of a portion of the node,
is necessary to examine lymph node architecture and stromal cellular elements
Combined modality treatment with chemotherapy and radiotherapy remains the
treatment of choice with attempts now being made to decrease treatment intensity
(specifically radiotherapy) in an attempt to minimize treatment-related side-effects.
Patients with HL have the highest incidence of such complications compared to children
with any other type of malignancy.

11.3 Tumour-lysis syndrome

High-count ALL (especially T-cell) and B-cell NHL (specifically Burkitt lymphoma) have
the potential for bulky disease -a high cell mass, which will undergo lysis with
treatment, resulting in the intracellular contents of potassium, phosphate and nuclear
debris being released into the circulation
Lymphoblast cells have four times the amount of phosphate compared to normal white
celIs
Uric acid crystals and phosphate (precipitatingout with calcium) crystals may cause
acute renal failure and the following:

Fluid overload t

Phosphate t

Potassium f

tUrea and creatinine

Calcium 5

Treatment involves:

Hyperhydration

Uric acid-lowering agents - allopurinol or uricozyme (urate oxidase)

Treatment of hyperkalaemia
Consideration of fluid filtration or dialysis

Haernatology and Oncology

1 4 Tumours of the CNS

The anatomical grouping together of brain tumours masks their diverse biological
differences
Brain tumours in children tend to be located in the posterior fossa, in the midline, have
greater differentiation and have slightly better survival figures than their counterparts in
adults
Brain tumours as a general rule do not metastasize out of the CNS
They are notoriously difficult to diagnose because of their varied and often non-specific
presentations. The mean time from onset of symptoms to diagnosis is 5 months.

Presenting symptoms o f brain tumours

Presenting symptoms % of children

Vomiting 65
Headache 64
Changes in personality and mood 47
Squint 24
Out-of-character behaviour 22
Deterioration of school performance 21
Growth failure 20
Weight loss 16
Seizures 16
Developmental delay 16
Disturbance of speech 11

Astrocytoma

Most commonly occurring brain tumour
Range from low-grade (benign)tumours, usually in the cerebellum, to high-grade
(malignant)tumours, usually supratentorial and brainstem
The glioblastoma multiforme tumour has a near-fatal prognosis

Medulloblastoma (primitiveneuroectodennaltumour (PNET)occumng in the

cerebellum)

20% of brain tumours
The most commonly occurring high-gradetumour
Commonly metastasizes within the CNS, and it is the one tumour that can metastasize
out of the CNS
Prognosis is in the region of a 50% 5-year survival

Essential Revisior~Notes in Paediatrics for the MRCPCH 2nd Edition

11.10 Malignant germ-cell tumours

Tumours derived from germ cells (cells giving rise to gonadal tissue) can be gonadal (30%
or extragonadal (7O0/0).

Extragonadal sites are the sacrococcygeal region, retroperitoneum, mediastinum, neck
and the pineal area of the brain
As gonadal tissue can give rise to any cell type, tumours derived from such cells may
express any cell line in any stage of differentiation. This gives rise to a range of tumours,
from an undifferentiated embryonal carcinoma to a benign and fully differentiated
mature teratoma
Serum markers a-fetoprotein and #&human chorionic gonadotrophin are useful in
diagnosing and monitoring disease state

11.11 Hepatoblastoma

Hepatoblastoma, an embryonal tumour of the liver, occurs in an otherwise normal liver
(compared to hepatocellular carcinoma) and generally presents in children under the
age of 2 years
Patients with Beckwith-Wiedemann syndrome or familial adenomatous polyposis have
an increased incidence of hepatoblastoma
There is evidence to suggest that low-birth-weight babies are predisposed to
hepatoblastoma
Treatment involves chemotherapy and surgery (partial liver resection or in some cases
liver transplantation)
Overall survival figures of 70-80% have been reported

11.12 Langerhans-cell histiocytosis

Langerhans cell histiocytosis is a clonal accumulation and proliferation of abnormal
bone-marrow-derived Langerhan cells. These cells, functioning as potent antigen-
presenting cells, together with lymphocytes, eosinophils and normal histiocytes form
infiltrates, in various organs, causing inflammatory tissue damage responsible for the
morbidity, and in some cases mortality, associated with this disease
Any age group may be affected
Patients can have localized disease (to skin, bone, or lymph node) or multi-system
disease (with spleen, lung, liver and bone marrow involvement carrying a worse
prognosis)

The disease course is unpredictable -varying from spontaneous regression to rapid

progression and death or repeated recurrences

Treatment is with a combination of corticosteroids, vinblastine, methotrexate, 6-

mercaptopurine

Hc3ematologyand Oncology

11.13 Haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) is a rare disease resulting from abnormal
proliferation of histiocytes (macrophages) in tissues and organs, and carries a high
fatality rate
Classified into familial or secondary HLH
Familial HLH is an autosomal recessive condition and involves a mutation in the peforin
gene (other gene defects are suspected but are not yet proven) resulting in a defect in
the natural killer cell and T-cell cytotoxic function. It is thought that this causes strong
immunological activation of phagocytes and mediators of inflammation, resulting in
multi-system pathology that may, if untreated, be fatal. Active treatment with
corticosteroids and chemotherapy is required in the acute phase followed by definitive
treatment with a bone marrow transplant
Secondary HLH, or its other commonly used term, macrophage activating syndrome, is
not inherited but has a similar pathophysiological process usually precipitated by
infection or rheumatological disorders
Typical findings of HLH are fever, hepatosplenomegaly, cytopenia,
hypertriglyceridaemia, coagulopathy, hypofibrinogenaemia, liver dysfunction, elevated
ferritin and serum transaminases, and neurological symptoms.

11.14 Role of bone marrow transplantation

The three broad areas in which bone marrow transplantation is a possibility are:

To replace a missing enzyme, e.g. mucopolysaccharidosis, adrenoleukodystrophy
To restore bone marrow function following high-dose or bone marrow ablative
chemotherapy, e.g. chemotherapy for neuroblastoma
To treat andlor immunomodulate a disease process, e.g. AML, juvenile CML (now

myelomonocytic -JMML), high-risk ALL (e.g. Philadelphia chiomosome +ve)

Bone marrow transplant can be:

Autologous- the patient receives hisher own bone marrow

Allogeneic -patient receives donated marrow from either a sibling (matched related .

donor) or an unrelated donor (matched unrelated donor)

The technique of harvesting peripheral-blood stem cells from a patient prior to ablative
chemotherapy and returning them post-chemotherapy now provides an alternative to bone
marrow harvesting. Currently, the use of cord-blood stem cells is becoming an option for
bone marrow transplant.

11.15 Principles of managing malignancy

The ultimate goal of oncological treatment is to cure the patient, i.e. to ensure the patient is
in life-long remission, while at the same time keeping treatment-related side-effects to the
minimum.

Essentia1 Revision Notes in Paediatric.5 for the MRCPCH 2nd Edition

The first step in achieving this goal in patients with haematological malignancies, such as
leukaemia, is to get the patient into remission. This is achieved with induction chemo-
therapy, usually over a 4-week period. To ensure that this remission is durable, further
treatment in the form of consolidation, intensification and maintenance chemotherapy is
required.

Patients with solid-tumour malignancies, on the other hand, generally require sequential
multimodal treatment. The tumour, depending on multiple factors including histological
type, stage, size, anatomical location, age of patient and degree of resectability, is either
surgically resected at the start of treatment, with adjuvant treatment in the form of chemo-
therapy andlor radiotherapy required thereafter to ensure complete eradication of remaining
tumour cells. If the localized primary tumour is too large to be safely resected or in cases of
metastatic disease, chemotherapy and/or radiotherapy are commenced to shrink the tumour,
thereby enabling resection at a later stage of treatment.

11.16 Late effects of cancer treatment

Chernotherapy

Second malignancies

Leukaemia and lymphoma are the two most likely secondary malignancies to occur -

particularly AML with topoisomerase II inhibitors (e.g. etoposide) while alkylators (e.g.
nitrogen mustard, cyclophosphamide) may cause either.

Cardiac
Cardiomyopathy is the most likely complication, particularly with anthracyeline-containing
chemotherapy, which is commonly used in treating solid tumours and, to a lesser extent,
leukaemia. This toxicity is exacerbated by thoracic radiotherapy.

Reduced fertility or infertility
Diminished fertility potential with increasing cumulative doses of alkylating chemotherapy
(particularly with procarbazine, which at high doses will render all males infertile), for
example in Hodgkin disease.

Pulmonary
Pulmonary fibrosis may result from bleomycin chemotherapy used, for example, in Hodgkin
disease and germ-cell tumours.

Neurocognitive
There are insufficient data at present to claim a definite association between chemotherapy
and neurocognitive difficulties, although this may very well exist. Methotrexate is the one
exception where an association has been made.

Auditory
Ototoxicity may result from platinum-containing agents, for example, cisplatinum and
carboplatinum, used commonly in the treatment of CNS and other solid tumours.

Renal
Decreased renal function as measured by the glomerular filtration rate (GFR) may be caused
by the same platinum-containing agents as above. In addition, a Fanconi syndrome with
electrolyte abnormalities may result from numerous chemotherapeutic agents.

Radiotherapy

The developing child is extremely susceptible to the damaging effects of radiotherapy,
particularly in the following areas:

Neurocognitive -especially in the younger child
Endocrine abnormalities - particularly growth and hypothyroidism
Second malignancies - particularly sarcomas and lymphoma

Musculoskeletal atrophy

Organ damage -for example, cardiac, lung, gastrointestinal

12. FURTHER READING

Bolton-Maggs PHB. 2000. Idiopathic thrombocytopenic purpura. Archives for Diseases in
Childhood 83, 220-2.
Cunningham MJ,Nathan DG. 2005. New developments in iron chelators. Review. Current
Opinions in Hematology 12, 129-34.
Lawson SE, Roberts IA, Amrolia PI Dokal I, Szydlo R, Darbyshire PJ. 2003. Bone marrow
transplantation for beta-thalassaemia major: the UK experience in two paediatric centres.
Review. British Journal of Haematology 1 20:2, 289-95.
Lilleyman J, Hann I, Blanchette V (Eds). 2000. Paediatric Haematology: London, Churchill
Livingstone.

Ouwehand WH, Smith C,Ranasinghe E. 2000. Management of severe alloimmune

thrornbocytopenia in the newborn. Archives for Diseases in Childhood Fetal Edition 82,
F173-5.

Pinkerton CR, Plowman PN (Eds). 1997. Paediatric Oncology. Chapman and Hall Medical.
Stiller CA, Eatock EM. 1999. Patterns of care and survival for children with acute
lymphoblastic leukaemia diagnosed between 1980 and 1994. Archives for Diseases in
Childhood 81, 202-8.
Tripp JH, McNinch AW. 1998. The vitamin K debacle - cut the Gordian knot but first do no
harm (Annotations). Archives for Diseases in Childhood 79, 295-7.
Williams J, Wolff A, Daly A, MacDonald A, Aukett A, Booth 1. 1999. Iron supplemented
formula milk related to reduction in psychomotor decline in infants from inner city areas.
BMJ 318, 693-8.

Chapter 12

Hepatology

Nancy Tan and Anil Dhawan

CONTENTS

1. Jaundice in infancy

1.I Bilirubin metabolism
1.2 Approach to a jaundiced infant
1.3 Unconjugated hyperbilirubinaemia
1.4 Conjugated hyperbilirubinaemia

I

2. Acute hepatitis

2.1 Acute infective hepatitis
2.2 Drug-induced liver disease

3. Acute liver failure

3.1 Paracetarnol poisoning

3.2 Wilson disease

4. Chronic liver disease and end-stage liver failure a'

4.1 Autoimmune hepatitis
4.2 Chronic viral hepatitis
4.3 Liver transplantation

5, Portal hypertension

6. Liver function test

7. The pancreas

5.1 Acute pancreatitis

5.2 Chronic pancreatitis

8. Further reading

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Essential Revision Notes in Paediatrics for the MRCPCH 2nd mition

1.2 Approach to a jaundiced infant

30-50% of normal term neonates experience jaundice
Physiological and breast-milk jaundice (unconjugated hyperbilirubinaernia)account for
the majority of cases in the first weeks of life
Approximately 1 in every 2500 infants is affected with cholestatic jaundice (conjugated
hyperbilirubinaemia)
Up to 15% of neonates can be jaundiced at 2 weeks of age and need to be investigated

1.3 Unconjugated hyperbilirubinaemia

The commonest causes include:
Physiological jaundice
Breast-milk jaundice
Haemolysis
Congenital hyperbilirubinaemia

Unconjugatedbilirubin is normally tightly bound to albumin
Kernicterus may result from high levels of unconjugated bilirubin

Management strategy is with phototherapy (if serum bilirubin > 250 pnol/l in term

babies), adequate hydration, and identification and treatment of the underlying causes

Physiologicaljaundice

5O0/0 of term and 80% of preterm babies are jaundiced in the first week of life
Jaundicewithin the first 24 h of life is always pathological and cannot be attributed to
physiological jaundice
The aetiology of physiological jaundice is not precisely known but may be related to
immaturity of bilirubin uridine diphosphate glucuronosyl transfe~ase(UGT) activity
Jaundicepeaks on day 3 of life
Treatment is by phototherapy or by exchange transfusion for severe hyperbilirubinaemia

Breast-milkjaundice

Occurs in 0.5-2OIi of neonates
Develops after day 4 (early pattern) or day 7 (late pattern)
Jaundicepeaks around the end of the second week
May overlap with physiological jaundice or be protracted for 1-2 months
Diagnosis is supported by a drop in serum bilirubin (350% in 1-3 days) if breast-
feeding is interrupted for 48 hours

Haemolysis

Commonly the result of isoimmune haemolysis (Rh, ABO incompatibility), red cell
membrane defects (congenital spherocytosis, hereditary elliptocytosis), enzyme defects
(glucose-6-phosphatedehydrogenase or pyruvate kinase deficiency) or of
haemoglobinopathies (sickle cell anaemia, thalassaemia)

Findings of jaundice in the presence of anaemia and a raised reticulocyte count would
necessitate further investigation for the cause of haemolysis

Inheriteddisordersof unconjugated hyperbilirubinaemia

This spectrum of disease depends on the degree of bilirubin UCT deficiency. Liver function
tests and histology are normal.

Gilbert syndrome
Mild deficiency (350% decrease of UCT activity) occurring in 7% of population
Polymorphism with TA repeats in the promoter region (TATA box) in Whites compared
to exon mutations in Asians on chromosome 2q37
Correlation between hepatic enzyme activity and serum bilirubin levels is unpredictable
because up to 40% of patients with Gilbert syndrome have a reduced red blood cell
life-span
Higher incidence of neonatal jaundice and breast-milk jaundice
Usually presents after puberty with an incidental finding of elevated bilirubin on blood
tests or jaundice after a period of fasting or intercurrent illness
More common in males
No treatment required, compatible with normal life span

Crigler-Najjar type I1
Moderate deficiency
May require phototherapy and phenobarbitone

Crigler-Najjar type I
Severe deficiency of UGT
High risk of kernicterus
Requires life-long phototherapy or even liver transplantation

Autosomal recessive inheritance. Both Gilbert syndrome and Crigler-Najjar type II can' also
have autosomal dominant transmission.

Congenital spherocytosis
Hereditary elliptocytosis
Infantile pyknocytosis

Erythrocyte enzyme defects
Glucose-6-phosphate dehydrogenase deficiency
Pyruvate kinase deficiency

Haemoglobinopathy
Sickle cell anaemia
Thalassaemia
Others

Sepsis
Microangiopathy

Haemolytic-uraemic syndrome

Ineffective erythropoiesis
Drugs
Infection
, En~losed~haematom
Polycythaemia

Diabetic mother s
Fetal transfusion (recipient)
Delayed cord clamping

DecreaseddeHvewyof unconjugatedbilirubin (inplasma)

Right-sided congestive heart failure
Portocaval shunt

Decreasedbilirubinuptake acrosshepatocytemembrane

Presumed enzyme transporter deficiency .
competitive inhibition

Breast-milk jaundice
Lucy-Driscoll syridro
' 0 Drug inhibition7(radio~~ntramsatte

Decreasedbiotransformation (conjugation)
Physiological jaundice
Inhibition (drugs)
Hereditary (Crigler-Najjar)

Type I (complete enzyme deficiency)
Type II (partial deficiency)

Gilbert disease
Hepatocellular dysfunction

Enterohepatic recirculation
Intestinal obstruction

Ileal a
Hirschsprung disease
Cystic fibrosis
Pyloric stenosis

Antibiotic administration

Brea

1.4 Conjugated hyperbilirubinaemia

Jaundice, dark urine, pale stools and hepatomegaly or hepatosplenomegaly

Baby may be acutely ill with hypoglycaemia, acid-base imbalance, electrolyte

imbalance, coagulopathy and liver failure

Biochemical definition is direct bilirubin > 20% of total

Top causes are:
'Idiopathic' neonatal hepatitis (40%)
Extrahepatic biliary atresia (25-30%)
lntrahepatic cholestasis syndromes (20%), e.g. Alagille syndrome, progressive
familial intrahepatic cholestasis (PFIC)
at -antitrypsin deficiency (7-1 0%)

Work-up o f conjugated hyperbilirubinaemia

Investigations Pathology

General investigations Type and level of jaundice
Liver function tests Degree of liver failure
Normal GGT levels (PFIC1, PFIC2 and
defects of bile acid synthesis)

Essenti,~/Revisio~N~otes in Pc?ecliatricsfor the MKCPCH 2nd Edition

-

Investigations Pathology

General investigations (continued) Marrow suppression (familial
Full blood count and haemophagocytic lymphohistiocytosis,
peripheral blood film lysosomal storage diseases)
Anaemia/acanthocytosis/thrombocytosis (HFI)
Vacuolated lymphocytes (Wolman disease)

PT/PTT, INR Coagulopathy (Iiver failure)

Vitamin K deficiency

Blood glucose Hypoglycaemia (Iiver failure, metabolic

disorders)

Renal function test Impaired renal function (liver failure,
Zellweger syndrome)

Lipid profile Hypercholesterolaemiaand
hypertriglyceridaemia (Wolman syndrome,
Alagille syndrome, PFIC)

Blood gas Metabolic acidosis (metabolic disorders)

Infections Urinary tract infection
Urine cultures

Herpes, toxoplasma, CMV, rubella, Intrauterine infection
syphilis, parvovirus B19 serology

Hepatitis B and A serology Hepatitis B and rarely hepatitis A
HIV

Enterovirus serology, CSF for PCR Neonatal systemic infection
or cultures

Blood cultures, CSF cultures Systemic bacterial infection

Endocrine High TSH, low T4, free T4 and T3
Thyroid function test (hypothyroidism, hypopituitarism)

Cortisol Low cortisol (hypopituitarism, septo-optic
dysplasia)

-- - -

Investigations Pathology

Metabolic Low level and PI ZZ (a-lantitrypsin

Serum a,-antitrypsin levels deficiency)

and PI type

Galactose-1-phosphate uridyl Deficiency (galactosaemia)
transferase (Gal-1-PUT)

Lactate Elevated (HFI, mitochondria1disorders)

Urine-reducingsubstances Positive (galactosaemia, HFI)

Ferritin Crossly elevated (neonatal
haemochromatosis)
a-fetoprotein Crossly elevated (tyrosinaemia)

Plasma amino acid, 3 x plasma tyrosine, phenylalanine,
urine amino acid
methionine, f urinary succinyDacetone
(tyrosinaemia)

Urinary organic acid Organic aciduria (tyrosinaemia, peroxisomal
enzyme deficiency, mitochondrial
hepatopathies)

Urinary bile acid intermediates Elevated (primary disorders of bile acid
synthesis, Zellweger syndrome)

Very long chain fatty acids (VLCFA) Elevated (peroxisomal enzyme deficiency)

Plasma transferrin isoforms Characteristic patterns in congenital

disorders of glycosylation

Sweat chloride Abnormal chloride levels (cystic fibrosis, PFIC)

Genetic testing Trisomy (trisomies 2 1 and 18)
Karyotyping Duplication of chromosome 22
(cat eye syndrome)
Specific mutations

Immune Anti-Ro and anti-La antibodies (neonatal
Autoantibodies lupus erythematosus)

Essential Revision Notes in Rjediatrics for the MRCPCH 2nd Edition -

-

Investigations Pathology
Biopsy
Liver Biliary atresia
Giant cell hepatitis
Lip lmmunostaining for PFlC
Skin biopsy and fibroblast Bile duct paucity (syndromic and non-
culture studies syndromic causes)
Gaucher cells (Gaucher syndrome)
Muscle biopsy Foamy histiocytes (Niemann-Pick, Wolman)
Bone marrow aspirate
Extrahepatic siderosis (neonatal
Imaging haematochromatosis)

Hepatobiliary ultrasound Sea blue histiocytes (Wolman disease)
Accumulation of intracytoplasmic
HlDA scan unesterified cholesterol (Niemann-Pick C)
Glucocerebrosidase deficiency (Gaucher)
Sphingomyelinasedeficiency (Niemann-Pick
A, B)
Acid lipase deficiency (Wolman)
a1,4-glycan-6-glycosyltransferase deficiency
(GSD IV)

Steatosis and ragged red fibres, respiratory
chain enzyme analysis (mitochondrial)

Gaucher cells (Gaucher)
'Foam' cells (~iemann-~ick'wolman)
Erythrophagocytosis (familial phagocytic
lymphohistiocytosis)

Adrenal calcification (Wolman)

- Triangular cord sign and absent or small
irregular gall bladder (biliary atresia)
Structural abnormalities (e.g. choledochal
cyst)

Normal excretion excludes biliary atresia.
Delayed or no excretion usually seen in
neonatal hepatitis

Hepatology

Investigations Pathology

Eye examination Cherry red spot (Niemann-Pick)
'Oil-drop' cataracts, intraocular haemorrhage
and retinal detachment (galactosaemia)
Corneal clouding, cataracts, pigmentary
retinopathy (Zellweger syndrome)
Coloboma (cat-eyesyndrome)
Posterior embryotoxon, optic disc drusen
(Alagille syndrome)

GGT, y-glutamyl transferase; PTlPlT, prothrombin timelpartial thromboplastin time; INR, international normal-
ized ratio; CMV, cytomegalovirus; HIV, human immunodeficiency virus; CSF, cerebrospinal fluid; PCR,
polymerase chain reaction; TSH, thyroid-stimulating hormone; T3, tri iodothyronine; HFI, hereditary fructose
intolerance; T4, thyroxine; PI, protease inhibitor.

Idiopathic neonatal hepatitis

Diagnosis of exclusion
Associated with low birth weight or prematurity
Histology

Hepatocellular swelling (ballooning),focal hepatic necrosis and multinucleated giant
cells
Bile duct proliferation and bile duct plugging are usually absent
Factors predicting poor prognosis
Severe jaundice beyond 6 months
Acholic stools
Familial occurrence
Persistent hepatosplenomegaly

goof0 do well with no long-term liver disease

Biliary atresia (BA)

Incidence: 1 per 16,000 live births

Slight female preponderance
Exact pathogenesis is unknown
25% associated with other congenital malformations
Anatomical variants

Type I -obliteration of the common bile duct

Type I1 -obliteration is extended to the common hepatic duct
Type Ill - obliteration of the entire extrahepatic biliary tree (commonest form)

Essential Revision Notes in Pacdi,~trics for the MRCPC'H 2nd Fdition

Type 1A ., Type 16

S" \

Type II
-

-,.-- - '/

The three variants of biliary atresia

Diagnosis is suggested by
Hepatobiliary ultrasound (fasting)-will show absent gallbladder or irregular outline
and triangular cord sign

Radionuclide imaging (phenobarbitonepriming) -no excretion indicates possible

biliary atresia; excretion indicates that it is not biliary atresia
Liver biopsy -expanded portal tracts with bile duct proliferation, bile plugs and

fibrosis
Gold standard for diagnosis is exploratory and operative cholangiography
Portoenterostomy (Kasai operation) should be offered to all children unless there is
decompensated liver disease
Between 70 and 80% achieve partial bile flow with 50% becoming jaundice free after
surgery
Ascending bacterial cholangitis follows the first year of surgery in 45-50%
It is a progressive disease even with a successful Kasai although prognosis may be better
if procedure is performed within 8 weeks of birth
Majority (8O0/0) require liver transplantation by 20 years of age
Fat-soluble vitamin supplementation is essential
Role of choleretic agents like phenobarbitone and ursodeoxycholic acid and steroids is
unproven

Alagille syndrome (arteriohepatic dysplasia)

Autosomal dominant
incidence is 1 per 100,000 live births
Defect of the IAG7 gene on chromosome 20pl2
lntrahepatic biliary hypoplasia
Characteristic facies (may not be prominent at birth)

Broad forehead
Deep-set eyes
Mild hypertelorism
Small chin

Skeletal abnormalities 3
Thoracic hemivertebrael'butterfly' vertebrae
I
Eye findings
Posterior embryotoxon
Retinal changes

Cardiac disease
Peripheral pulmonary artery stenosis
Other congenital cardiac malformations

Intrauterine growth retardation and faltering growth with severe malnutrition occur in
50%
Others

Renal disease
Delayed puberty or hypogonadism
Mental retardation, learning difficulties or psychosocial dysfunction
Vascular abnormalities
Hypothyroidism and pancreatic insufficiency
Recurrent otitis media, chest infection
Hypercholesterolaemia
Variable phenotype, severe liver disease may require liver transplantation

Progressivefamilial intrahepatic cholestasis (PFIC)

Group of inherited diseases which present as neonatal hepatitis, faltering growth, pruritis
and progressive liver disease, requiring liver transplantation in the first few years of life.

Byler disease
Mutation of the FlCl gene on chromosome 18q21-22
Pancreatitis, persistent diarrhoea, short stature and sensorineural hearing loss

Normal GGT, serum cholesterol
Elevated serum bile salts, sweat chloride
Low chenodeoxycholic acid in bile

Mutations on chromosome 2q24, bile salt export pump (BSEP) gene
Normal GGT

Mutations in the P-glycoprotein MDR-3 gene (ABCB4)

* Elevated GGT

Bile phospholipids 15% of normal

a1-Antitrypsindeficiency

Commonest inherited cause of conjugatedjaundice
Autosomal recessive

Essen ti^ l Revision Notes in E7ccJiatric.c for the ib1KC-PCH I rx-l Edition

Incidence is 1 in 1600-2000 live births
Mutation at the protease inhibitor (PI) locus on chromosome 14
More than 75 variants are known but not all mutations result in disease
The most common disease phenotype is PI ZZ, homozygous for a point mutation in
which glutamic acid is replaced by glycine at position 342. This causes abnormal
folding of the a1-antitrypsin molecule so that it becomes trapped in the endoplasmic
reticulum, causing liver damage
Associated with intrauterine growth retardation
Hepatomegaly at presentation is common
Cholestasis may be severe enough to produce totally acholic stools
Approximately 2% of infants will present with vitamin K-responsive coagulopathy
Diagnosis is from

low a1 -antitrypsin levels

phenotype (PI) by isoelectric focusing
Replacement with recombinant a1-antitrypsin is not helpful because abnormal protein
continues to accumulate in the endoplasmic reticulum
Prognosis - 50% of children presenting with neonatal hepatitis develop chronic liver
disease with half of them requiring a liver transplant in the first 10 years of life.

Causesofconjugatedja

Infections

Bacterial

Urinary tract infection
0 Septicaemia*

Syphilis
Listeriosis
Tuberculosis

Parasitic

Toxop~asmosis

* Malaria

Viral

Cytomegalovirus
Herpes simplex virus*
Human herpes virus type 6*
Herpes zoster virus
Adenovirus
Parvovirus*
Enterovirus
Reovirus type 3
Human immunodeficiency virus
Hepatitis B virus*
? Hepatitis A
? Rotavirus

Metabolic disorders

Carbohydrate metabolism

Galactosaemia*
Fructosaemia*
Glycogen storage type 4
Congenital disorders of glycosylation*

Protein metabolism (amino acid)

Tyrosinaemia*
Hypermethioninaemia
Urea cycle defects (arginase deficiency)

Lipid metabolism

Niemann-Pick disease (type C) ,

Wolman disease*
Cholesterol ester storage disease

Bile acid disorders*

Disorders of oxid

Endocrinediso

Chromosomaldisorders

Down syndrome
Trisomy E
Patau syndrome

Alagille syndrome
Byler syndrome (PFIC 1)
Bile salt export protein defect (BSEP defect, PFlC 2 )
Multidrug resistant 3 deficiency (MDR 3, PFlC 3)
Hereditary cholestasis with lymphoedema (Aagenaes syndrome)

Essential Revisio~N? otes in Paedic3tricstbr the MRCPCH 2nd Edition

Metals andtoxins

Neonatal haemochromatosis*
Copper-related cholestasis*
parentera1 nutrition
Drugs

bematological disordms

kfaemophagocytic lymphohistiocytosis*
Langerhans' cell histiocytosis

Inspissated bile syndrome

BiIiarykeedisorders

Biliary atresla
Mucus plug

Bile dud st.mosis/stricture

Spontaneous perforation of common bile duct

Neonatal sclerosing cholangitis
Caroli disease

2. ACUTE HEPATITIS

Acute hepatitis is characterised by liver inflammation and necrosis. The underlying trigger
varies, including infective, autoimmune, toxic (e.g. drugs) and metabolic causes.

Hepatology

2.1 Acute infective hepatitis

Acute infection of the liver may result from many pathogens. Complete recovery from an
infection is dependent on the host's ability to eliminate the infective agent, resolution of
liver inflammation and prevention of infection by effective antibody production.

Symptoms in hepatitis may include:

Prodrome of malaise
Anorexia
Nausea
Vomiting
Fever
Tender hepatomegaly
Splenomegaly
Lymphadenopathy
Rash
Jaundice

Viruses are the commonest cause of acute infective hepatitis.

Essential Revision Notes in R~eciiatric-stor the MRCPCH 2nd Edition

HepatitisA infection

Commonest form of acute viral hepatitis, accounting for 20-25OlO of all clinically
apparent hepatitis world-wide
Picornavirusfamily, RNA virus
Orofaecal route of spread
Incubation period 2-6 weeks
Infectivity from faecal shedding begins during the prodromal phase, peaks at the onset
of symptoms and then rapidly declines. Shedding may persist for up to 3 months

Usually asymptomatic, less than 5% of infected people have an identifiable illness

Symptomatic infection increases with age of acquisition

Mortality is 0.2-0.4% of symptomatic cases and is increased in individuals > 50 or
< 5 years

Morbidity and mortality are associated with:
Fulminant hepatic failure
Prolonged cholestasis
Recurrent hepatitis
Extrahepatic complications
Neurological involvement - Guillain-Bar& syndrome, transverse myelitis, postviral
encephalitis, mononeuritis multiplex

Renal disease -Acute interstitial nephritis, mesangioproliferative

glomerulonephritis, nephrotic syndrome, acute renal failure
Acute pancreatitis

Haematological disorders -autoimmune haemolytic anaemia, red cell aplasia,

thrombocytopaenic purpura
Non-specific elevation of conjugated bilirubin and aminotransferase enzymes. Degree of
elevation does not correlate with severity of illness or likelihood of c~mplications
Confirmation of diagnosis relies on detection of:

Anti-HAV IgM - indicator of recent infection; peak levels occir during acute illness

or early convalescent phase; persists for 4-6 months after infection

Anti-HAV IgG -appears early; peaks during convalescent phase; persists lifelong,

conferring protection
Supportive symptomatic treatment and adequate hydration. Complete recovery is usual
within 3-6 months
Active immunization with a formaldehyde-inactivatedvaccine is available
Passive immunization with human normal immunoglobulin offers up to 6 months of
protection and is effective if given within 2-3 weeks of exposure

2.2 Drug induced liver disease

Most drugs are lipophilic and are detoxified and excreted in bile. This is achieved by oxidation
or demethylationby the cytochrome P450 enzyme system or conjugated by glucuronidation or
sulphation by specific transferases. Intermediate metabolites can be potentially harmful and
may be detoxified by the binding of gluthathione, catalysed by gluthathione-S-transferase.

Mechanism of drug-induced liver disease

Direct hepatotoxicity -usually dose dependent

Hepatology

Adverse drug reaction - unpredictable and idiosyncratic

Spectrum of drug-induced liver disease
Enzyme induction without disease

Acute hepatitislhepatocellular necrosis (commonest)- acetaminophen, methyldopa,

isoniazid, halothane, phenytoin

Cholestasis - erythromycin, cotrimoxazole
Granulomatous hepatitis -carbemazepine
Drug-induced chronic hepatitis - methyldopa, nitrofurantion
Fatty liver - microvesicular (aspirin, valproate, tetracycline) or macrovesicular

(amiodarone)

Fibrosis - methotrexate, vitamin A, actinomycin D
Vascular disorders -sinusoidal dilatation (oestrogen) or veno-occlusive disease (6-

mercaptopurine)

Hepatic tumours -oral contraceptives

Diagnosis of drug-induced liver disease is usually based on circumstantial evidence and
exclusion of other causes
Withdrawal of the causative drug is the most effective treatment
Specific therapy is available for paracetamol (N-a~etylc~steine)

3. ACUTE LIVER FAILURE

Acute liver failure or fulminant hepatitis is rare in childhood. Mortality is 70% without
appropriate management or liver transplantation. It is the indication for liver transplant in
about 10-20% of paediatric recipients in major transplant centres. One-year survival rate is
in the range of 60-70%.

It is a multisystemic disorder, defined as:

Severe impairment of liver function (INR > 2 and unresponsive to vitamin K)

fencephalopathy (not essential to make diagnosis)

Associated hepatocellular necrosis
No previous underlying recognizable liver disease

The commonest causes of acute liver failure are:

In the neonate:
Neonatal haemochromatosis
Disseminated herpes simplex infection
Haemophagocytic lymphohistiocytosis
Metabolic causes

in the older child:
Viral hepatitis
Metabolic causes
Acetaminophen toxicity
Autoimmune hepatitis
Wilson disease
Idiopathic

Essential Revision Notes in Paediatrics for the MRCPCH 2nd Fdition g--

Causes of acute liver failure -5----za
Infective -2-

Viral --i
-e3
Viral hepatitis-A, B, B + D, E
'-=a4S-3$
Non-A-E hepatitis (seronegative hepatitis)
Adenovirus, Epstein-Barr virus, cytomegalovirus eZ-sZ
Echovirus -3-2
Varicella, measles viruses
Yellow fever %is

teptospirosis -5s

Drugs 4=E E s

Acetaminophen -
Halc "
ae
Non-steroidal anti-inflammatory drugs
-j
P- -h.e-n-#v--to-i-n--

Sodium valnrnate

Antiretroviral drugs ---
Synergistic drug interactions
-3-
Isorriazid + rifam~icin
--
Trimethoprim + iulfarnethoxazole
Barbiturates + acetaminophen --f
+Amoxycillin clavulinic acid

Toxins

Amanita phalloides (mushroom poisoning)
Herbal medicines
Carbon tetrachloride
Yellow phosphorus
Industrial solvents
Chlorobenzenes

Metabolic

Galactosaemia
Tyrosinaemia
Hereditary fructose intolerance
Neonatal haemochromatosis
Niemann-Pick dise
Wilson disease
Mitochondria1c)rtop
Congenital disorders of glycosylation
Acute fatty liver of pregnancy

Budd-Chiari syndrome

Causes of neonatal acute liver failure

Perinatal herpes simplex virus infection
Neonatal haemochromatosis
Galactosaemia
Tyrosinaemia
Haemophagocytic lymphohistiocytosis
Septicaemia
Mitochondria1cytopathies
Congenital disorders of glycosy lation
Severe birth asphyxia

Biochemistry of acute liver failure

prothrombin time (does not improve with parenteral vitamin K)
f direct and indirect bilirubin

aminotransferase activities (AST), then J, as patient deteriorates

t serum ammonia

Complications of acute liver failure

Encephalopathy
May be absent or difficult to recognize in children

Stage 1 - mild confusion/anxiety, disturbed or reversal of sleep rhythm, shortened

attention span, slowing of ability to perform mental tasks (simple addition or
subtraction). In young children, irritability, altered sleep pattern, unexplained bursts
of excessive crying

Stage 2 - drowsiness, confusion, mood swings with personality ihanges,

inappropriate behaviour, intermittent disorientation of time and'place, gross deficit in
ability to perform mental tasks. In young children, excessive sleepiriess, inability to
interact with or recognize parents, lack of interest in favourite toys or activities

Stage 3 - pronounced confusion, delirious but arousable, persistent disorientation

of time and place, hyperreflexia with a positive Babinski sign
Stage 4 - comatose with or without decerebrate or decorticate posturing, response
to pain present (stage 4a) or no response to pain (stage 4b)
Renal insufficiency/failure
10-1 5% have renal failure, 75% have renal insufficiency as a result of hepatorenal
syndrome, direct kidney toxicity or acute tubular necrosis
50% require haemodialysis or haemofiltration support
Cardiovascular
Early hyperdynamic circulation with decreased peripheral vascular resistance
Late haemodynamic circulatory failure as a result of falling cardiac output,
depression of brainstem function or cardiac arrythmias
Pulmonary

Aspiration, intrapulmonary shunting, atelectasis, infection, intrapulmonary
haemorrhage, respiratory depression or pulmonary oedema
Metabolic
Hypoglycaemia
Acid-base imbalance

Respiratory alkalosis, metabolic alkalosis and metabolic acidosis

Electrolyte imbalance
Coagulopathy

1synthesis of clotting factors
fibrinloysis and 1 clearance of activated factors and fibrin degradation products

Thrombocytopenia (correlates with risk of haemorrhage)
Infections

Poor host defences, poor respiratory effort, multiple invasive lines and tubes

Others
Adrenal hyporesponsiveness, pancreatitis, aplastic anaemia

Management of acute liver failure involves management of complications, and elucidation
and treatment of the cause.

Discuss/refer to a liver centre
No sedation unless patient is on assisted ventilation
Ventilate for respiratory failure, agitation with grade I or II encephalopathy or severe
encephalopathy (grade 111 or IV)
No coagulation support unless bleeding or for invasive procedures
Monitoring should involve

Continuous oxygen saturation monitoring

At least 6-hourly - neurological observations/vital signs (may need invasive
monitoring)/urine output/blood glucose (maintain > 4 mmolll)
At least 12-hourly - acid-base/electrolytes/PT/PTT, INR .

Gastric pH (>5)

Daily or more often - haemoglobin and platelet count

Fluid balance
75% maintenance with 0.4S0/~(or less) saline with dextrose
Maintain circulating volume with colloid, crystalloids or blood products as

appropriate

Haemofiltration if there is renal failure

Coagulation
Fresh frozen plasma when bleeding

Keep platelet count > 50 X 1 0 9 / d ~

Drugs
H2 blockers or proton pump inhibitors (prevent gastrointestinal bleed)
Lactulose to achieve two or three stools per day
N-acetylcysteine as experimental for non-paracetamol-induced acute liver failure

Intravenous broad-spectrum antibiotics and anti-fungals as prophylaxis

Esser?tic~R1evision ,Nett, in P,/~~-/i~,strtic~rthe t t /Rd 'PCH 2llr:r'Ecdjtjcm &-a

Nutrition -------=-A----.------x----------.-------.-..

Enteral feeding (1-2 g protein/kg per day) -?------.--

Parenteral nutrition is rarely indicated a--=-- -i
Specific therapy =-

~cetaminophentoxicity - N-acetylcysteine (100 rng/kg per day) A

Hereditary tyrosinaemia - NTBC =-a
Neonatal haemochromatosis - iron chelation and antioxidant cocktaillN-
-=-----I---.5-z--
acetylcysteine (100 mg/kg per day intravenous infusion)/selenium (3 pglkg per day
intravenous)/desferrioxamine (30 mg/kg per day intravenous)/prostaglandinE l (0.4- ----
0.6 pg/kg per hour intravenous)/vitamin E (25 U/kg per day intravenousloral) -
Mushroom poisoning - benzylpenicillin (1,000,000 U/kg per day) or thiotic acid -I-.--!--.
(300 mg/kg per day)
Hepatic support with liver assist devices such as molecular adsorbent recirculating
system (MARS) are still under investigation
Emergency liver transplantation

3.1 Paracetamol (acetaminophen) poisoning

Mainly one large dose in a suicidal attempt, occasionally accidental over-ingestion over
several days.
Direct dose dependent hepatotoxic effect
Metabolism

95% Conjugated to sulphate 1
lucuronide '
Paracetamol

s%& Cytochrome P450

I IN-acetyl-p I IExcretion in urine
benzoquinonemine

Rapidly bound to NAPQl is a highly reactive metabolite which
intracellular glutathione binds covalently to cell macromolecules,
impairing mitochondria1and nuclear function
Urine excretion as leading to cell death
mercapturic acid
-I -----
I ---
-
Metabolism of paracetamol -

Hepatology

With overdosage, gluthathione is depleted and NAPQl is not detoxified
Acute ingestion of 150 mg/kg is likely to cause significant hepatotoxicity
Triphasic clinical course

Stage 1 (0-24 h) - nausea, vomiting, anorexia
Stage 2 (24-48 h) - liver enlarged and tender from hepatic necrosis

Stage 3 (48-96 h) - acute liver failure

If patient survives stage 3, resolution of liver dysfunction within 4 days to 2 weeks
Prognosis is bad if:

Arterial pH < 7.3
PTT > 100 s or INR > 6.6, creatinine > 300 mmolll, grade Ill-IV encephalopathy (all

three)
Management

Discuss with a liver centre

N-acetylcysteine infusion 100 mg/kg per day until INR < 1.5

3.2 Wilson disease

An autosomal recessive disease with incidence of 1 in 50, 000; caused by a mutation of the
ATP7B gene at 13q14.3 (commonest H I069Q).

Clinical presentation is as follows:

Asymptomatic
Family screening

Hepatic (5-12 years)

Insidious onset with vague symptoms followed by jaundice
Abnormal liver function tests
Acute hepatic failure
Acute hepatitis
Chronic liver disease
Cirrhosis and portal hypertension
Neurological (second decade)
Deterioratingschool/work performance
Mood/behaviour changes

Incoordination (e.g. deterioration of handwriting)

Resting and intention tremors
Dysarthria, excessive salivation
Dysphagia
Mask-like facies
Others
Sunflower cataracts
Acute haemolytic anaemia
Renal, cardiac, skeletal abnormalities

Diagnosis is suggested by:
plasma caeruloplasmin (<200 mg/l)

J. urinary copper

> 5 pmo1/24 h (baseline)
> 25 ymo1124 h (after penicillamine challenge)

f liver copper concentration (>250 pg/g dry weight of liver)
Mutation analysis
Kayser-Fleischer rings

Treatment

Penicillamine 20 mglkg per day (gradually increased from 5 mg/kg per day)
Pyridoxine 10 mg/week
Other drugs include: triethylene tetramine dihydrochloride (trientine), zinc sulphatel
acetate, tetrathiomolybelate
Liver transplantation

fulminant hepatic failure
chronic, progression of hepatic dysfunction despite treatment

4. CHRONIC LIVER DISEASE AND END-STAGE LIVER FAILURE

Chronic liver diseases of childhood lead to cirrhosis and/or cholestasis. The resulting fibrosis
and regenerative nodular formation distorts the liver architecture and compresses hepatic
vascular and biliary structures, resulting in portal hypertension and a vicious cycle of events
that worsen the hepatic injury.

Diagnostic considerations

Confirming the presence and type of liver disease

Compensated - may be asymptomatic

Decompensated - presence of liver synthetic failure and occurrence of
complications

End-stage -a persistent rise in bilirubin, prolongation of the INR > 1.3, persistent
fall in serum albumin to < 35 g/l, faltering growth despite intensive nutritional

support, severe hepatic complications such as chronic hepatic encephalopathy,
refractory ascites, intractable pruritus, or recurrent variceal bleeding despite
appropriate medical management
Determining aetiology
Assessing complications

Complications and management

Malnutrition and growth failure
Specialized formula (/Na fMCT (medium chain triglycerides))
Supplement vitamins A, D, K, and E
f Caloric density of enteral feeds
Continuous nocturnal nasogastric or nasojejunal feeds

Parenteral nutritional support
Portal hypertension

Major cause of morbidity and mortality (30-50%)

Portal vein pressure > 5 mmHg or portal vein to hepatic vein gradient > 10 mmHg

splenomegaly -+hypersplenism

oesophageal, gastric and rectal varices
ascites

encephalopathy

Prevention and management of oesophageal variceal bleeding

sclerotherapy
variceal ligation

surgical porto-systemic shunts
transjugular intrahepatic porto-systemic shunt (TIPS)

oesophageal transection and devascularization

pharmacotherapy, e.g. propanolol
Factors that predict bleeding

portal vein-hepatic vein gradient > 12 mmHg

large, tense varices
red wale marks, red spots on varices
severity of underlying liver disease

Ascites
50% of patients will die within 2 years of developing ascites

Treatment

Step 1 -sodium restriction (1-2 mmollkg per day)
Step 2 -spironolactone
Step 3 - fchlorthiazide/frusemide and fluid restriction

Spontaneous bacterial peritonitis can occur insidiously and causes high mortality
Coagulopathy

Vitamin K malabsorption/deficiency
Vitamin K-dependent coagulation protein deficiencies (factors II, VII, IX and X)

Hypofibrinogenaemia and dysfibrinogenaemia
Thrombocytopenia
Consumption coagulopathy
Parenteral vitamin K and transfusion of fresh frozen plasma (prothrombin time

> 40 s) or platelets (4i0 X 1 0 ~ l l )

Hepatopulmonary syndrome
Triad of:
Liver dysfunction

lntrapulmonary arteriovenous shunts

Arterial hypoxaemia - arterial oxygen pressure of < 70 mmHg in room air
and an alveolar/arterial gradient of > 20 mmHg

Type 1 -functional shunt
Type 2 - anatomical

Should be suspected if there is increasing history of breathlessness, cyanosis,

clubbing and platypnoea
Site and extent of shunt is assessed by:

Essential Revision Notes in f<~ediLltricfo-r~the A.1K(Y(:H 2nd Fclitir M I

arterial blood gas analysis

technetium 99m-labelled macroaggregated albumin (""'Tc MAA) study
contrast echocardiogram
Definitive treatment is with liver transplantation

Portopulmonary hypertension

Mean pulmonary artery pressure > 25 mmHg, pulmonary capillary wedge pressure
of < 15 mmHg in the absence of any secondary causes of pulmonary hypertension

Comparisonof hepatopulmonarysyndromeand portopulmonary

hypertension

Hepatopulmonarysyndrome Portopulmonaryhypertension
lntrapulmonary vasodilatation lntrapulmonary vasoconstriction
Alveolar arterial gradient usually normal
Alveolar arterial gradient > 20 mmHg
Mean pulmonary artery pressure
Normal mean pulmonary artery pressure
> 25 mmHg
Perform shunt fraction study
Trial of 10O0/0 0 2 Perform right heart catheterization
Often reversible with liver transplantation Vasodilator therapy trial
May not reverse with liver transplant
Poor prognosis: p ~ 0 2< 300 mmHg Poor prognosis: pulmonary artery
on 100% 0 2 > 45 mmHg
pressure
Histology: pulmonary artery normal Histology: pulmonary artery abnormal;
concentric medial hypertrophy

Hepatorenal syndrome

Diagnostic criteria

oliguria: urine output < 1 mllkg per day
fractorial excretion sodium < 1OO/
urine-to-plasma creatinine ratio < 10

t1glomerular filtration rate, creatinine

absence of hypovolemia

other kidney pathology excluded

Type 1 rapidly progressive with poor prognosis
Type 2 less precipitous loss of renal function

Mortality of > 90% with severe liver disease

Reversed with liver transplantation

Causesof chronic liver disease in children

Onset in infancy
Structural

Extrahepatic biliary atresia
Alagille syndrome, biliary hypoplasia
Choledochal cyst, tumours, stones
Storage/metabolic diseases
Carbohydrate defects

galactosaemia, fructosaemia, glycogen storage Ill and IV
Amino acid defects

tyrosinaemia, urea cycle disorders
Metal storage defects
Lipid storage diseases

Gaucher disease, Niemann-Pick type C
Fatty acid oxidation defects
Peroxisomal disorders
Zellweger syndrome
Mitochondria1disorders
Progressive familiar intrahepatic cholestasis syndrome
Total parenteral nutrition-associated cholestasis
Cystic fibrosis liver disease
Haematological
Langerhans cell histiocytosis
Infection/inflammation
Neonatal hepatitis

Hepatitis B and hepatitis C

Onset in childhood

All of the above and
Autoimmune liver disease

Autoimmune hepatitis
Autoimmune sclerosing cholangitis
Sclerosing cholangitis
Drugsltoxins (e.g. chemotherapy-inducedveno-occlusive disease)
Fibropolycystic disorders
Chronic hepatic venous outflow obstruction
Hepatic vein thrombosis
Budd-Chiari syndrome
Veno-occlusive disease
Cardiac cirrhosis

4.1 Autoimmune hepatitis I

Autoimmune hepatitis has a 75% female preponderance. Other autoimmune disorders are !E
present in 20°h and 40% of first-degree relatives may also have autoimmune disease.
1
Clinical presentation is variable:
7
Acute hepatitis
Insidious onset i
Portal hypertension

Diagnostic criteria are based on:

Serum non-organ-specific autoantibodies
Type 1

Anti-nuclear antibody (ANA)
Anti-smooth muscle antibody (SMA)
Type 2
Anti-liver-kidney microsomal (LKM-1)
Up to 20% may not have antibodies detectable at presentation
Serum biochemistry

7 Aminotransferases

Serum IgG

> 1.5 X normal

Liver histology
Absence of

Markers of viral infection and metabolic disease
Excessive alcohol consumption
Use of hepatotoxic drugs

Treatment involves:

Corticosteroids
Azathioprine for poor response or as steroid sparing
Liver transplant for fulminant hepatic failure or failure of medical therapy

Response to therapy (International Autoimmune Hepatitis Group) is defined as follows:

Marked improvement of symptoms and return of serum ASTIALT, bilirubin and
immunoglobulin levels to completely normal within 1 year and sustained for at least a
further 6 months on maintenance therapy

f

Liver biopsy specimen during this period showing minimal activity

OR

Marked improvement of symptoms together with at least 50% improvement of all liver
test results during the first month of treatment, with AST/ALT levels continuing to fall to
less than twice the upper limit of normal within 6 months during any reduction towards
maintenance therapy

f

Liver biopsy within 1 year showing minimal activity
Relapses are common (occurring in 40%).
IgG levels and autoantibody titres correlate with disease activity.

4.2 Chmnic viral hepatitis

Hepatitis B and C viruses (HBV and HCV) are the top causative agents

HepatitisB (aDNA hepadnavirus)

World-wide prevalence of 5% (chronic carriers)
Transmission

Perinatal - HbeAg-positive mothers have a 70-90% risk of transmission to their
offspring

Horizontal - parenteral, sexual and environmental transmission

Symptomatic acute hepatitis
Complete resolution occurs in 90%
Lifelong immunity

Asymptomatic chronic infection (HbsAg-positivefor at least 6 months)
90% progress to chronic liver disease
Three stages - immune tolerance; immune clearance; and residual non-replicative
infection

Chronic infection may lead to cirrhosis and hepatocellular carcinoma

Serological markers of HBV

Host HBV status ALT HBV DNA cAb sAg sAb 'eAg eAb

Acute t Detectable IgM then + - + -

IgG

Chronic N High I@ +- +-
Immune tolerance Detectable I&
Immune clearance f Undetectable IgG +- +-
Non-replicative Undetectable +- -+
Resolved N IgG - -I- - +

N

"eAg is absent in pre-core mutant.

Immunization

Maternal status Anti-HBV HBV vaccine

sAg eAg eAb immunoglobulin 3 doses within 12 h, and
200 IU within 12 h at 1 and 6 months
++ Y Y
+-+ N Y
+-- Y Y

Treatment

Immunomodulation - interferon-a, pegylated interferon

Antivirals - lamivudine, famciclovir, adefovir

Not much paediatric experience
50% of patients seroconvert with therapy (adult data)
Liver transplantation for fulminant HBV disease, chronic liver disease, hepatocellular
carcinoma

Hepatitis C infection (an RNA flavivirus)

World-wide prevalence is 3%
Transmission

From blood transfusion or plasma-pooled products
Vertical transmission (rare)
Usually asymptomatic but leads to cirrhosis over years

* One of the commonest indications for liver transplant in adults

Serology
Anti-HCV antibody positive
HCV RNA positive in two consecutive samples

Treatment
Interferon-a monotherapy
Interferon-dribavarin combination therapy
Paediatric experience is minimal

70% of patients seroconvert with therapy (adult data)

4.3 Liver transplantation

Indications for transplant
Acute liver failure
Decompensated chronic liver disease
Liver-based metabolic diseases
Liver tumours

Relative contraindications
Severe systemic sepsis
Malignant hepatic tumours with extrahepatic involvement

Severe, irreversible extrahepatic disease (e.g. structural brain damage, severe
cardiopulmonary disease not correctable with surgery)
Severe systemic oxalosis with cardiac involvement (haemodynamic instability)
Mitochondria1 cytopathies with multisystem involvement
Giant cell hepatitis with Coomb's positive haemolytic syndrome
Source of organ
Deceased donor
Living related donor
Type of graft
Whole liver
Segmental graft
Procedure
Orthotopic
Auxiliary
Lifelong immunosuppression is required
Calcineurin inhibitors

Ciclosporine
Tacrolimus
Renal sparing drugs
Mammalian target of rapamycin (mTOR) inhibitor

Sirolimus (mTOR inhibitor)
Mycophenolate mofetil
Azathiaprine

Interleukin-2 receptor antibodies -basiliximab, daclizumab
Others -anti-thymocyte globulin, OKT3

Steroids
Post-operative complications

Early
Graft failure (primary non-function)
Surgical (intra-abdominal haemorrhage, hepatic artery thrombosis, portal vein

thrombosis
Drug side-effects (renal failure, hyperglycaemia, hypertension)
After 1st week
Acute rejection
Biliary leaks and strictures
Persistent wound drainage
Sepsis
Late
Epstein-Barr virus infection
Side-effects of immunosuppression (renal failure, hyperglycaemia, hyperlipi-

daemia)

Post-transplant lymphoproliferative disease

Graft rejection
Late biliary strictures, hepatic artery thrombosis or portal vein thrombosis

Essential R e v i s i ~ rN~otes i17 PC2edi,~trichs r t h ib~fRCpc!? 2nd Edific~n

Recurrent disease (HBV infection, malignant hepatic tumours)

De novo autoimmune hepatitis

Patient survival:
1-year - 80-90%

5-year - 70-80%

10-year- 70-75%

5, PORTAL HYPERTENSlON

The portal vein contributes to two-thirds of the liver's blood supply. Portal venous pressure
is a product of blood flow from the splanchnic circulation and vascular resistance within
the liver.

Portal hypertension is defined as a portal vein pressure > 5 mmHg or portal vein to
hepatic vein gradient > 10 mmHg

A rise in portal pressure leads to splenomegaly and development of portosystemic
collaterals and varices

A gradient of > 12 mmHg is associated with the development of oesophageal varices.

The junction between the mucosal and submucosal varices in the lower 2-5 cm of the
oesophagus is the usual site of variceal bleeding
Not all portal hypertension is a result of intrinsic liver disease although chronic liver
disease is the commonest overall cause. Portal vein occlusion is the most frequent
extrahepatic cause of portal hypertension

Causesof portal hypertension *

Fre-hepatic (portalvein occlusion)

General factors
Developmental malformation
Septicaemia
Thrombophilia
Myeloproliferative disorders
Paroxysmal nocturnal haemoglobinuria

Protein C deficiency

Protein S deficiency
Antithrombin Ill deficiency
Factor V Lieden mutation
Anti-phospholipid antibodies

ctor IIgene mutation ((320210A)

rnocysteinaemia

Local factors
Umbilical sepsis, catheterization, infusion of irritant solutions
Intra-abdominal sepsis and portal pyaemia
Abdominal trauma
Structural lesions
Cholangitis/choledochal cyst
Pancreatitis
Malignant disease/lymphadenopathy
Splenectomy

Intrahepatic
Pre-sinusoidal

Hepatoportal sclerosis
Neoplasia
Hepatic cyst
Sinusoidal
Chronic liver disease and congenital hepatic fibrosis
Post-sinusoidal
Veno-occlusive disease

Post-hepatic

Budd-Chiari syndrome
Chronic constrictive pericarditis
Right ventricular failure

Presentation is typically with acute gastrointestinal haemorrhage, splenomegaly or as
part of the manifestation of chronic liver disease
In long-standing disease, varices around the common bile d.uct may cause portal
hypertensive biliopathy resulting in bile duct dilatation and obstructive jaundice
Rarely, pulmonary hypertension may coexist with portal hypertension, more often in
children with chronic liver disease
Anaemia, leukopenia and thrombocytopenia may result from hypersplenism
Management

Portal hypertension associated with chronic liver disease
variceal banding or sclerotherapy

liver transplantation if variceal bleeding is uncontrolled with therapy

Extrahepatic portal hypertension
variceal banding or sclerotherapy
portocaval or mesoportal shunt

Pharmacotherapy is not proven in children

LIVER FUNCTION TEST

This reflects the severity of liver dysfunction but rarely provides diagnostic information on
individual diseases.

EssentiC2R/ evision Notes in Paediatrics for the MRCPCH 2nd Edition *=
g
L----------=&---qgE
-= - - 1 =
$3gh

Bilirubin B

Conjugated (direct) hyperbilirubinaemia I
Specific to liver disease
!
Conjugated fraction > 20% of total bilirubin is indicative of hepatic dysfunction
51
Unconjugated (indirect) hyperbilirubinaemia
i
Normal bilirubin levels does not exclude liver cirrhosis
I
Arninotransferases
i
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
Most common tests of liver cell dysfunction t
lntracellular enzymes
Indicate hepatic necrosis I
AST is produced in the cytosol and mitochondria of the liver, heart, skeletal muscle,
kidney, pancreas and red cells 5
ALT is found in the cytosol of liver and muscle cells and so is more liver specific
In isolated AST or ALTelevations, a normal creatine kinase level is helpful in ruling out i
muscle pathologies
1
ALT: AST ratio > 1 is suggestive of fibrosis in some liver pathologies like steatohepatitis

and chronic hepatitis C
There is no correlation between the enzyme levels and the severity of disease
Levels may be normal in compensated cirrhosis or end-stage liver disease

Alkaline phosphatase (ALP)

Found in liver, kidney, bone, placenta and intestine
Reflects biliary epithelial damage
Children have higher ALP levels than adults (bone isoenzyme)
Levels are low in zinc deficiency

Gamma-glutamyltransferase (GGT)

Present in biliary epithelia, hepatocytes, renal tubules, pancreas, brain, breast and small
intestine
Reference range is age related. Normal levels in newborns are five to eight times higher

than those of adults but reach adult values by 9 months

Most sensitive test for hepatobiliary disease but cannot differentiate between extra- or
intrahepatic biliary disease
May be normal in familial intrahepatic cholestasis, bile acid synthesis disorders, ARC
syndrome (arthrogryposis, renal and cholestasis) and very advanced liver disease

Albumin concentration

Reflects the synthetic capacity of the liver
Produced in the liver
Long half-life, so is not decreased in acute liver injury

Levels < 35 g/dl in chronic liver disease suggest decompensation

462