Puo

1. DR R N Sharma MD
Professor Emeritus PIMS
Fmr( Prof & HOD Medicine GMC KTYM, AIMS Kochi,&
PIMS)
Fmr Chair person Postgraduate studies MG University
Fmr Dean Faculty of Medicine MG University

3.  A practical problem for every physician
 for PGs also
 Some cases are very tough– A gujarathy lady
 Different hospitals(5+3) fever unrelenting weight
loss / 8 months/ seen by GS in my absence
nofindings/ Next week Bilateral 6 th N palsy
 Diagnosis?
 A theory question on approach to PUO can be
expected

5. What is at the end of tunnel?

6.  In a fever case many a time we have no idea what
is going to happen at the end

10. Data from discharge summary
65 yr old Mr Devan admitted to a High Tech Hospital
at our Cosmopolitan city of fever aches and pains
over the joints and headache of 2 months duration
duration.
Evaluated in 3 different hospitals prior to that
admission
Since fever continued they approached the high tech
well equipped hospital

11.  Fever was perceived day and night
 It varied from 100degree F to 102degree F
 No rigor Chills
 No urinary symptoms, respiratory symptoms ,
chest pain
 Complained of body ache athralgia of various joints
 He complained of intermittent headache for > 2
months

12.  Headache was diffuse in nature felt all over the
head
 Waxing and waning
 Not infrequently pt awakened by head ache
 Most of the time he suffered from the ache
subsiding with paracetamol
 He never vomited
 Combing his hair was uneventful

13.  No change in the headache by posture , turning in
bed or by stooping down
 There were no cranial nerve symptoms, no
rhinorrhoea
 No visual disturbance/no redness of eyes
 No symptoms to suggest long tract symptoms
 No cardiac, respiratory, Urinary symptoms

14.  Appetite was dull
 Pt lost 5 Kg weight in the last 3 months
 Was constipated

15.  General examination Non contributory
 CVS
 RS
 GIT
 Nervous system
 Testicles
NAD

16.  Total duration nearly 2months
 Last 15 days in High tech hospital
 All possible investigations done meticulously and
scientifically and in orderly manner

17.  Giving only summary of investigations

18. Parameters
TC 12100 14000 14500 14300
DC P 82/-L13/E1- /sM4 P80/L20 P79/L21 P78/L22
Hb 9.0gm% 8.7 gm% 8.5% 8gm%
ESR 92 100 120 130
CRP 150 156 155 150
P smear Normochromic
normocytic / Shift
to left/
thrombocytosis
Platelet count 484K 500k 526K 556K
Reticount 1% 1% 1% 1%
LDH 150 170 160 155

19. Parameters
S BillirubinTotal 0.7 mg%
S Billirubin direct 0.4 mg/dL
SGPT 13 20 20 25
SGOT 15 25 30 18
Alkaline phosphatase 275 ( 38-126) 290 300 290
GGT 75(7-47 iu) 70 67 77
Albumin 4.9 gm%
Globulin 2.9 gm%
PT 14.3.13.3
INR 1.
APTT
S electrophoresis No M Band

20. Urea 26
Creatinine 1,1
Na 136
K 4.5
Cl 100
HCO3 24

21. Blood culture
Widal test negative
Blood Culture No growth No growth No growth No growth
HIV negative
HBsAg negative
HCV negative
IgM EBV negative
IgM CMV negative
Brucella agglutinin negative
Antilepospiral
Antibody IgM
negative
PF antigen negative
Malarial parasite negative negative negative negative

22.  Xray Chest WNL
 USG WNL
 CT Thorax Abdomen WNL
 MRI brain N
 Bone marrow non contributory ( cytology & culture
AFB culture pending)

23.  Echo N done twice

24. ENT consultation------ noncontributory
Neurology consultation-------- noncontributory
 LP done CSF normal

25.  Started Emperically on Piperacillin Tazobactum+
Doxy
 Fever and head ache contd during hospital stay
 PET Scan done noncontributory
 Pt had relief of fever for 3 days and got discharged
 Suggestion to follow up
 Fever reappeared after few days

26.  Pt consulted a pulmonologist
 He suggested ATT provisionally.
 The patient was not happy to receive a label of
tuberculosis

27.  He was brought by relatives to another physician
XYZ

28.  Fever continued
 Nearly two months
 Fever unabated
 Many investigations repeated drawn blank
 Pt got discharged
 LFT rpt showed Elevated Alkaline Phosphatase

29.  Discharge summary
 Suggest further follow up in OP and evaluation

30.  Too huge topic
 Will go through what general clinical examination
should be done and their significance

31. Salient points from discharge summary
 Fever Headache several weeks
 Headache no vomiting
 Anaemia
 Raised ESR CRP
 Alkaline phosphatase high
 Cultures negative

32. Fever headache new onset
persistent daily headache
ESR high CRP high USG normal
No neck stiffness Alkaline phosphatase
high
CT Thorax N CT Abdomen
N
No focal findings in any
system
Normochromic
normocytic Shift to left--
blood picture
MRI Brain N
Repeated cultures negative PET Scan noncontributory
LP normal
All cultures negative

33.  How to approach the problem?

34. Evaluation Physical examination
Investigations
Pranams to My teachers
GK Warrier Sir
Geevarghese sir
Nathew Parackal sir
Sathyadas sir

35.  Well worked up case in a good hospital
 A challenging case for physician

36.  Physicians approach

37.  Difficult case how they would have done it
 As physician
 Huge topic
 Requires more than 3 hrs
 Restricting to History & physical examination and
Abnormalities in investigations All minimal

38. Infections
Noninfectious
Inflammatory/
immunological/CTD
Neoplasm
Drug fever
Factitious fever

39.  S. gallolyticus. Colonic tumour / endocarditis

40. History
General
Examination
Head to
Toes
examination
All systems
meticulously
Investigations
focused Blood
and imaging
Invasive
Clinical
correlations

41.  History

42. History
 Presenting
 Past
 Personal
 Family
 Drugs
 Travel
 Promiscuous contacts

43. Detailed history
 Meticulous history to be taken
 Contact with fever cases
 Animals birds
 Travel
 Sexual history / multiple partners/ protected sex

44. History

46. Story of IAS officer
close friend of
HOD

47. Trekking
Ticks

48.  Fever and Headache dominant symptoms

49.  Pt had almost daily headache with fever
 The headache is daily happening
 Something similar to NDPH
 NDPH can be due to any infection

52.  What are the causes of New onset Daily
Persistent Headache? NDPH

53. NDPH occurs due to causes like
 intracranial tumours
 Benign intracranial
Hypertension
 subdural haematoma
 Chronic meningitis
 Medication overuse
headache
 Persistent CSF leak(
CSF Hypotension)
 Cerebral venous
thrombosis
 Post traumatic
headache

54. Other causes of NDPH
 Epstein-Barr virus / CMV
 Salmonella.
 E. coli.
 Dengue fever.
 COVID-19.
 Meningitis or encephalitis
 Any infection

55.  Since the patient is running fever intracranial
tumour. SDH, BIH,CSF hypotension , Subarachnoid
Haemorrhage , Cerebral venous thrombosis are
unlikely
 Left with infections that can cause headache
 Severe headache + fever- meningitis to be ruled
out
 MRI no meningeal enhancement CSF normal

56.  Meningitis ruled out
 Left with infections all blood cultures were negative
 Pt has been given provisionally broad spectrum
covering Gram positive gram negative and aerobic
and anaerobic infections

57.  Though Broadspectrum antibiotics given
 Abscesses somewhere cant be ruled out
 Antibiotics may not penetrate
 Fever was continuing
 Abscess was ruled out as PET scan did not show
any abscess

59. Why Head to foot examination?
 Any abnormality to be sought, Picked up and
focused clinically
 No stone unturned
 Simple findings can lead to diagnosis
 We should not trivialise any abnormality even in
this high tech era

60. Head to foot Examn Scalp
 Scalp -Palpate whole scalp running your finger
 any swellings/
 combing if necessary
 Superficial temporal artery
 Look for any eschar
 Any skin ulceration
 Any nodule --- Sarcoidosis ( by biopsy)

62.  Learning points
 Scrub typhus is difficult to diagnose as the presentation is very
non-specific. An eschar at the site of bite is pathognomic and
the single most useful diagnostic clue.
 Eschar is painless, non-itching lesion and is common in
warm damp areas of body where skin surfaces meet or
clothes bind (perineum, groin and axilla). It develops
following the bite of mites which is also painless. Hence, though
it can clinch the diagnosis, it often goes unnoticed.

63. Figure 1.
(A) Three days from symptom onset (SE03): central yellowish vesicle with mild whitish scale, and peripheral erythematous patch. (B) SE05: central vesicle turned into brown to black-
colored crusts and scales are increased. (C) SE06: formation of typical eschar lesion having central black crusts and conspicuous erythematous patch with overlaying scale. (D) SE08:
well-established eschar composed of three concentric components; innermost black crust outlined by inner scaly line, middle erythematous patch, and outermost whitish scaly layer.
(E) SE14: shrinkage of central crusts and diminished peripheral scale. (F) SE17: central crust completely disappeared, and changed into central scar-like whitish area with peripheral
erythematous area showing prominent vascular pattern. (G) SE20: dull reddish-brown hyperpigmentation.

64. Head to foot Eyes
 Proptosis Lymphoma
 Scleritis
 RA/Vasculitis ( ANCA) Syphilis
 Tuberculosis
 Lyme disease
 Herpes zoster
 Aspergillis
 Sarcoidosis
 Inflammatory bowel disease

65. Head to foot Eyes
 Iridocyclitis
 Viruses CMV, EBV etc
 Syphilis
 TB
 Toxoplasmosis
 Catscratch diseases
 Lyme disease
 Behcet
 SLE
 IBD
 PAN
 Wegners

66. Head to foot-- Eyes
Sarcoidosis Affecting the Lacrimal Gland

67. Hoagland sign
Early transient periorbital
oedema( upper lids)
bilateral an early transient
sign

68.  A Boy running fever
 developed visual loss
 What is the probable diagnosis?
Cat scratch
disease

69. Head to foot Eyes

70. Head to foot Eyes
Color fundus photo of the right eye showing
multiple healed choroidal tuberculomas.

71. Head to foot Eyes
Bacterial Endocarditis

72. Head to foot Eyes- Fundus
Multiple Roth's spots on the fundus of a patient
with acute leukemia are evident as hemorrhages
with a white center.

73. Head to foot – Eyes Fundus oculi
anterior ischemic optic neuropathy seen in giant
cell arteritis

74. Head to foot- Eyes
 Ocular sarcoidosis can involve any part of the eye
and its adnexal tissues, and may cause
 uveitis,
 episcleritis/scleritis,
 conjunctival granuloma,
 optic neuropathy,
 lacrimal gland enlargement and orbital
inflammation.

75. Head to foot ------eyes
Fundus sarcoidosis

76. Head to foot -----------------oral cavity
GCA

77. Head to foot--------- oral cavity

78. Head to foot --- oral cavity
Snail track
ulcers

79. Head to foot examination
 typical rash Bilaterally symmetrical erythematous
coppery red rash which elicited
 Buschke-Ollendorff sign
 What test to order?
 Secondary syphilis
 Also Fever + such a rash+ periosteitis - S2

80. Head to foot oral cavity--- Dental
Infection Pyorrhoea

81. Head to foot -- Ears

82. Head to foot -- Ears
 A PUO in a boy no diagnosis after liver biopsy,
bone marrow and broad spectrum antibiotics/ Past
history revealing CSOM
 Mastoidectomy ------- fever melted

83. Head to foot -- Ears
 A case of pyrexia of unknown origin (PUO) in a 54-year-old lady is described.
 She subsequently developed ocular and aural inflammation suggestive of
relapsing polychondritis (RP) with immediate clinical improvement following
steroid therapy.
 PUO is an unusual presenting feature of RP.

84. Head to foot- neck

85. Head to foot---- neck
 Lymphadenopathy
 Need not be present initially
 May appear over the course any day
 May be too tiny initially
 concentrate on all groups


86. Head to foot---- neck
 appearance may indicate
 infections--- EBV, CMV TB etc
 Systemic inflammatory/
immunological SLE/RA/Sarcoidosis
serum sickness
 Neoplasms lymphoreticular
HL/NHL
 Drug induced Phenytoin

87. Head to foot----- neck

88. Head to foot--- neck
 A radiologist investigated for puo
 Her symptoms were severe arthralgia and
bodyache
 Pain in the ear Right/ ENT consultation  No ENT
problem
 All PUO investigations drawn blank
 What will you look for?
 Thyroid tenderness / Probe tenderness

89. Head to foot--- neck Thyroid
 Carefully palpate for thyroid tenderness
 May not be present initially
 can appear at any time of PUO
 Clues neck pain body ache arthralgia fever
 Ear pain ( referred pain)Throat pain ENT surgeon
everything normal consider thyroiditis
 As usual daily or alternateday examination
 Another clue– Probe tenderness

90. Head to foot--- neck Thyroid
 Order TFT
 what will it show?
 What is the next investigation ?
 Thyrotoxicosis vs Hyperthyroidism
 Low uptake in thyroiditis
 Hyperthyroidism also can present as low grade
fever
T4 increased
T3 increased
TSH dectreased

91. Head to foot ---neck
 A 74-year-old woman presented fevers and right
neck pain.
 Carotid artery tenderness
 bilateral temporal headache with scalp allodynia
 Diagnosis?
 Giant Cell Arteritis with Carotidynia

92. Head to foot--- Axillae

93. Head to foot--- Axillae
 Lymphnodes
 part of generalised lymphadenopathy
 Infections , neoplasms
 In a puo unsolved important to get a biopsy

94. Head to foot--------------------Chest
 A Computer techie 24 yr old
 Tall build thin
 Running fever 2 months in three different hospitals
 All investigations drawn blank
 Referred to Medical college
 He and father came in
 He was sick

95. Head to foot--------------------Chest
 He started story telling / One minute was over
 He said I want to lie down
 Me and father helped him out on to the
examination couch and he managed to lie down
 The right sided limbs suddenly became flacid and
no movement His RLL got externally rotated/ Left
angle of mouth deviated/ No speech

96. Head to foot--------------------Chest
 Right Hemiplegia Right UMN facial palsyAphasia
 “ Bolt from Blue”
 Typical of
 Embolic stroke
 Diagnosis on clinical grounds
 Embolism from endocarditis / What will you do
next
 Auscultate

97. Head to foot--------------------Chest
 S1 loud Tachycardia
 Made to sit up with the help of father and mother
 Got a short systolic murmur which as not present
in supine posture
 My eyes ran from head to foot
 Fingers – mild clubbing

98.  Diagnosis
 Marfanoid habitus loud S1 Short systolic murmur
on upright posture
 We can miss
 Carefully auscultate for MVP CLICK also AR
 If in doubt always ask for ECHO

99. Head to foot-- Pulse
 20 yr old girl running high fever
 All culture and imaging all normal
 She developed loss of radial pulse and brachial
pulse
 She developed altered sensorium
 What is the possibility? What investigation next
Any guess?

102. Head to foot -- hand
Osler node on ring
finger as well as more
subtle nodes seen on
the little and middle
finger.

103. Head to foot -----Hands
A and B
Janeway lesions,
C splinter
haemorrhages

104. Osler node

105. Head to foot --- Hand
Fever+ clubbing
IE

106.  Janeway lesions (nontender pink or purple,
irregular, macular lesions occurring mostly on
palmar and plantar surfaces due to septic emboli)
 Osler nodes (tender erythematous nodules on
hands and feet due to immune complex
deposition);
 most commonly affected sites are fingertips, but
sides of fingers, palms, soles, and toes may also be
affected

108. Head to foot --- Scrotum Genitalia
 Often reluctant and shy to offer history of pain or
swelling
 Proactively ask for
 testicular swelling –fever- Tuberculosis /
Brucellosis/ PAN
 Scrotal abscess

109. Head to foot ---- PR / PV
 Case of a HOD’s daughter admitted with sepsis/
Fever continuing/ Tons of antibiotics
 “ No focal source”/
 Went into shock
 pt had pain from admission
 After 10 days pt reported pain around anus - 
 PR done  bulge on rectal wall Ischiorectal
abscess
 Drained  fever subsided

110. Head to foot ---- PR / PV
 Lesson --- overcome noncompliance of the pt by
appropriate pt friendly interventions
 Do you want to tell me something delicate which
you think may be useful to help us to solve the
problem

111. Head to foot --- Back Gluteal area
 Story of Mundakkayam lady investigated elsewhere
no cause found
 sent to medical college
 Thoroughly investigated with liver biopsy Bone
marrow – All unrewarding
 By matter of intution I had asked HS to examine
gluteal region for tenderness daily
 After 3 weeks of hospital stay HS informed me of
tenderness on the buttock


112. Head to foot --- Back Gluteal area
 Tenderness increased /Abscess popped up /One to
two Ozs of pus drained
 Fever subsided
 She was admitted in a hospital for fever / the
original fever subsided/ She received inj
paracetamol in the buttock that got infected
 Overlap with inj abscess fever

113.  40 yr old male
 Running fever one
month
 Worked up in two
hospitals
 All investigations for
fever –ve
 ECHO CT abdomen
thorax N
 Third tertiary care
hospital
 All blood parameters
repeated / P
smear/USG abdomen N
 Xray chest N

114.  CT Thorax N
 CT abdomen
done
 CT abdomen
Revealed a
diagnosis
 Any guess PGS

117. Head to foot----Entire back
Gibbus
Spinal
tenderness
Patches
nodule

118. Papular sarcoid

119. Janeway lesion

120. Osler’s nodes and Janeway lesions

123. PAN small renal artery aneurism

124. Janeway lesions

125. ESR elevated
Infections
Acute Rheumatic fever SLE Technical
Endocarditis PMR Others
osteomyelitis GCA Ruptured ectopic pregnancy
Septic arthritis Acute MI Anemia
PID Malignancy Renal disease with azotemia
TB Paraproteinemia Administration of dextran or
oral contraceptives
Acute hepatitis WM
Inflamatory disease MM
RA Cryoglobulinaemia

126.  Elevated ESR does not give us Much clue

127.  Low ESR (rarely important, but useful for exams)
 Polycythaemia.
 Hypofibrinogenaemia.
 CCF.
 Poikilocytosis.
 Spherocytosis.
 Sickled cells

128.  ESR falling from an elevated level should alert one
to the possibility of HLH/ MAS


129. PDC9 (Potentially Diagnostic Clues)
Harrison’s
 ESR or CRP
 Hb
 TLC DLC platelet count
 Electrolytes
 Creatinine
 Total protein
 Electrophoresis
 Alkaline phosphatase,
 AST,
 ALT
 LDH
 Creatinine Kinase
 ANA
 RA factor
 urine analysis
 Blood culture
 urine Culture
 Cheat Xray
 USG abdomen
 Tuberculin Skin test or IGRA

130.  Anemia

131. Anaemia
 Normochromic normocytic
 shift to left of WBC series
 Shift to left indicates infection or inflamation

132.  Normo chromic normocytic

133. Causes of normochromic normocytic
anaemia MKSAP

134. ?
 Left shift of granulocytes (ie, abundant band forms,
metamyelocytes, myelocytes) may be due to severe
infection/sepsis or chronic myeloid leukemia (CML),
 while the presence of significant number of myeloid blasts
suggests acute myeloid leukemia (AML)
 occasionally, blasts can be seen with extreme
inflammation/bone marrow stimulation.

135.  All the above categories require consideration

136. Elevated alkaline phosphatases
Infections
Liver diseases
Systemic conditions
Malignancy
Drugs

137. Alkaline phosphatase
 Liver
 Bone
 intestines,
 kidneys, and
 white blood cells.
 Pregnancy
 Growing age

138. ALP
 metastatic bone disease and bone fractures)
 cholestatic liver disease
 cholestatic liver disease—for example,
 primary biliary cholangitis (PBC),
 primary sclerosing cholangitis (PSC),
 common bile duct obstruction, intrahepatic duct obstruction (metastases),
drug-induced cholestasis
 Right heart failure( cholestasis elevated ALP and /or Billirubin)

139. Isolated elevation of ALP with elevated GGT
=
Hepatic origin of alkaline phosphatase

140. Isolated elevation alkaline
phosphatase(Harrison 21 st)
 cholestasis ,
 hepatic infiltration by Tumor or granulomata.
 primary biliary cholangitis,
 sclerosing cholangitis,
 Hodgkin’s disease,
 diabetes,
 hyperthyroidism,
 congestive heart failure,
 amyloidosis.

141. Isolated Alk
phosphatase elevation
Normal Billirubin&
normal Transaminase
Early Cholestasis
PBC
PSC
DM
CCF
Amyloidosis
Hyperthyroidism
Hodgkins
Infiltrations
Tumour
Granulomata
Often NOT always

142.  Hepatic granuloma

143. Infections with granulomatous hepatitis
 TB
 MAI
 NTM
Leprosy
 Brucella
 Yersenia
 Listeria
 Q fever
 Syphilis
 Fungus
 Schistosomiasis
 Leishmaniasis
 VIRUSES
 Hepatitis C virus
 Epstein-Barr virus
 Cytomegalovirus

144. Systemic conditions with Granuloma liver
 Autoimmune hepatitis
 Biliary cirrhosis, primary
 Chronic granulomatous disease
 Common variable immunodeficiency
 Inflammatory bowel disease
 Juvenile idiopathic arthritis
 Sarcoidosis
 Systemic lupus erythematosus
 Wegener granulomatosis

145. Systemic conditions with Granuloma liver
 Autoimmune hepatitis
 Biliary cirrhosis, primary
 Chronic granulomatous
disease
 Common variable
 immunodeficiency
 Inflammatory bowel disease
 Juvenile idiopathic arthritis
 Sarcoidosis
 Systemic lupus
erythematosus
 Wegener granulomatosis
 GCA
 PMR
 Sarcoidosis

146. Liver granuloma Drugs and chemicals
 Allopurinol
 Barium
 Carbamazepine
 Mebendazole
 Methyldopa
 Antimicrobial agents:
norfloxacin,
 penicillin
 Chemotherapeutic agents
 Phenytoin
 Pyrazinamides
 Sulfasalazine
 Talc
 Quinine

147. Malignancy and hepatic granuloma
 Hodgkins
 NHL

148. In summary
 Fever headache
 Raised ESR
 Elevated ALP

150. Consulted another
physician
Physician reverted to
third year student
level
Detailed history taken
thread bear
Persistent Headache No
vomiting
No CN symptoms
Looked sick
Walks only with support
System Symptom review
non contributory
Re-examined thoroughly
No neck stiffness
No Physicals
History reviewed
No dysuria/ Haemoptysis
Diarrhoea

151. Anything else you have failed to mention? Pt was
asked
What about your eating?

152. Pt mentioned a funny symptom?

153. Pt gets pain in tongue and jaw while eating

154. Now the diagnosis written on the face

155.  Pt was asked to chew Chewing gum
 It reproduced Pain in the jaw and tongue

156. Reexamined
No scalp tenderness
Fundi N

157. PUO
65 yrs
Headache
Wt loss
All imaging including MRI PET ScanN
Elevated Alkaline phosphatase

158. Planned Biopsy
He was on DAPT for CAD for 10 yrs
Therefore Consent not given
The drug was started
next day onwards Pt was perfectly alright

159. Diagnosis;-
GCA

160. Jaw / tongue claudication
Temporal arteritis
Takayasu’s arteritis
Mc Ardles disease( Myophosphorylase )

161. Giant cell arthritis PET Scan

162. Harrison’s
 ESR CRB Hb TC DC
 Platelet count
 Electrolytes
 RFT
 Total proteinA/G
 Protein
electrophoresis
 Alkaline
phosphatase
 LDH/ ALT /AST/CPK
 ANA
 RA FACTOR
 Urine analysis
 Blood culturesX3
 Urine culture
 Xray Chest USG
abdomen
 Mantoux

164. History emphasis
 Travel,
 Contacts animal
 and insect exposure,
 medications,
 immunizations,
 family
 history,
 cardiac valve disorder

165. Examination Emphasis
 Fundi, oropharynx,
 temporal artery,
 abdomen, lymph nodes,
 spleen, joints, skin, nails,
 genitalia, rectum or
 prostate, lower limb
 deep veins

166. Investigation emphasis
 Imaging, biopsies,
 sedimentation rate,
 skin tests

167.  Alkaline phosphatase is the most important single
laboratory test; may be elevated in
 temporal arteritis,
 hypernephroma,
 thyroiditis,
 tuberculosis.

170.  Of the NIIDs,
 adult-onset Still’s disease,
 large-vessel vasculitis,
 polymyalgia rheumatica,
 systemic lupus erythematodus (SLE), a
 sarcoidosis
 are common diagnoses in patients with FUO.

171. On alkaline phosphatase
 Alkaline phosphatase (ALP) is produced mainly in the liver (from the hepatocyte canalicular
membrane with a significantly lesser contribution from the biliary epithelium) but
 is also found in abundance in the bone and in smaller quantities in the intestines, kidneys, and
white blood cells.
 Levels are physiologically higher in childhood, associated with bone growth, and in pregnancy
due to placental production.
 Pathologically increased levels occur mainly in bone disease
 (e.g., metastatic bone disease and bone fractures)
 And
 cholestatic liver disease—for example, primary biliary cholangitis
 (PBC), primary sclerosing cholangitis (PSC), common bile
 duct obstruction, intrahepatic duct obstruction (metastases),
 and drug-induced cholestasis
 Right heart failure( cholestasis elevated ALP and /or Billirubin)