Specific signs Bald tongue (Fig. 2C.4)

Koilonychia (Fig. 2C.5)

Blue sclera (Fig. 2C.6)

Peripheral smear Microcytic hypochromic red cells

Other specific

investigation

Iron studies, BM staining for iron, stool/urine for occult blood, and endoscopy

Megaloblastic anemia

Specific symptoms Tingling and numbness

Sensory ataxia

Specific signs Glossitis, knuckle pigmentation (Fig. 2C.7), absent deep tendon reflexes (DTRs), sensory loss, and

positive Romberg’s test

Peripheral smear Macrocytic RBC’s, hypersegmented neutrophils, and pancytopenia

Other specific

investigation

Serum vitamin B12

levels, red cell folate levels, bone marrow examination, and schillings test

Anemia of chronic disease

Specific symptoms Symptoms of chronic kidney, liver disease, and connective tissue disorders

Specific sign Hypertension, arteriovenous (AV) fistula—chronic kidney disease (CKD)

Signs of liver cell failure—chronic liver disease (CLD)

Signs of rheumatoid arthritis, systemic lupus erythematosus (SLE), etc.

Peripheral smear Normocytic normochromic anemia ± pancytopenia

Other specific

investigation

Renal function test, liver function tests, autoantibodies, and raised serum ferritin

Hemolytic anemia

Specific symptoms History of associated jaundice, developmental delay, family history positivity, recurrent blood

transfusions, and gallstones

Specific signs Triad of anemia + jaundice + splenomegaly

Hemolytic (Chipmunk) facies (Fig. 2C.8)

Hyperpigmentation (Fig. 2C.9), short stature, and leg ulcers.

Peripheral smear Microcytic hypochromic (thalassemia)

Microspherocytes (hereditary spherocytosis)

Sickle cells

Reticulocytosis

Other specific

investigation

Hemoglobin electrophoresis, Coombs test, sickling test, and osmotic fragility

Aplastic anemia

Specific symptoms Recurrent infections

Bleeding manifestations

Specific signs Signs of pancytopenia

No organomegaly

Peripheral smear Pancytopenia

Other specific

investigation

Bone marrow examination

Cytogenetics

Fig. 2C.4: Bald tongue.

Fig. 2C.5: Koilonychia

Fig. 2C.6: Blue sclera. Fig 2C.9: Hyperpigmentation of palm.

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Fig. 2C.7: Knuckle pigmentation.

Fig. 2C.8: Chipmunk facies.

ICTERUS

Definition

Yellowish discoloration of skin, mucous membranes, sclera, and blood vessels secondary to increased

bilirubin (bile pigments have affinity for elastin tissue).

Sites to Look for Jaundice

Sclera (Fig. 2C.10)

Sublingual mucosa

Oral cavity

Palms and soles

Skin.

Scleral icterus is a term commonly used but from a histopathologic perspective, it is a misnomer.

Bilirubin has a high affinity for elastin, which is an abundant protein in the conjunctivae as well as

the superficial, fibrovascular episclerae, but not the sclerae proper. One actually is observing

icterus of the bulbar conjunctiva against the white background provided by sclera. Conjunctival

icterus is often the first sign of hyperbilirubinemia. Hence we recommended the use of term

“conjunctival icterus” instead of “scleral icterus”.

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Why unexposed sclera/conjunctiva seen

When the sclera/conjunctiva is exposed to sunlight, bilirubin gets converted to its soluble form

and hence exposed part of conjunctiva may not reveal mild jaundice.

Yellowish discoloration can be normally seen in the exposed parts of sclera/conjunctiva which is

called as muddy sclera/conjunctiva.

Fig. 2C.10: Demonstration of icterus. Fig. 2C.11: Dark yellow icterus.

Serum Bilirubin Levels and Jaundice

0.3–1.2 mg/dL Normal

1.2–2.5 mg/dL Latent jaundice (generally not appreciated on clinical examination)

>2.5 mg/dL Clinically appreciated

Yellowish discoloration without jaundice:

Hypercarotenemia (here sclera is not affected)

Hypothyroidism (due to decreased metabolism of carotene)

Excessive exposure to phenols/nitric acid

Quinacrine intake.

Grading

No standard grading system is available; however, few examiners prefer the following:

Mild jaundice Only sclera becomes yellow

Moderate jaundice Skin also becomes yellow

Differentiating Type of Jaundice Based on Scleral Color

Lemon yellow Most likely hemolytic jaundice

Dark yellow (Fig. 2C.11) Obstructive jaundice

Greenish dark yellow Longstanding obstructive jaundice due to oxidation of bilirubin to biliverdin

Differentiating Jaundice Based on Clinical and Laboratory Findings

Prehepatic (hemolytic) Hepatic Posthepatic

(obstructive/surgical)

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History

Urine Normal Yellow Yellow

Stools Normal Normal Pale clay like

Pruritis - ± ++

Examination

Bradycardia - - +

Pallor Present Absent Absent

Jaundice Mild Moderate Severe

Splenomegaly Present Variable Absent

Palpable gallbladder ± - ++

Features of liver cell

failure

Absent + (early feature) ± (late feature)

Laboratory data

Serum bilirubin UCB↑ UCB↑ + CB↑ CB↑

Serum enzymes LDH ↑ AST ↑

ALT ↑

ALP ↑

Urine bilirubin - + +

Urine urobilinogen + + -

Examples

Examples Thalassemia

Sickle cell anemia

Spherocytosis

Malaria

Immune hemolytic

anemias

Hepatitis (viral/alcoholic/drug

induced)

Infiltrative disorders

Ischemic hepatitis

CBD stones

Helminths in the CBD

Carcinoma—head of pancreas

Primary biliary cirrhosis

Primary sclerosing cholangitis

(AST: aspartate aminotransferase; ALP: alkaline phosphatase; CB; conjugated bilirubin; CBD: common

bile duct; LDH: lactate dehydrogenase; UCB: unconjugated bilirubin)

CYANOSIS

Definition

Bluish color of skin and mucous membranes resulting from an increased quantity of reduced

hemoglobin (deoxygenated) or hemoglobin derivatives (methemoglobin or sulfhemoglobin) in the small

vessels of those tissues.

Criteria

Deoxy Hb >5 g% or abnormal Hb (metHb or sulf Hb) ± SaO2 <85%.

Classification

True cyanosis:

Central cyanosis

Peripheral cyanosis

Mixed cyanosis.

Pseudocyanosis.

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Etiology of Cyanosis

1. True cyanosis

a. Central cyanosis

Cardiac

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Cyanotic heart diseases

Truncus arteriosus

Transposition of great arteries

Total anomalous pulmonary venous connection (TAPVC)

Tetralogy of Fallot

Tricuspid atresia

Ebstein’s anomaly

Eisenmengerization (tardive cyanosis)

Pulmonary Asthma

Chronic obstructive pulmonary disease (COPD)

Cor pulmonale

Respiratory failure of any cause like pneumonia, tension pneumothorax, massive pleural effusion, and acute

pulmonary edema

Others High altitude

Polycythemia

Enterogenous or pigment cyanosis (replacement cyanosis)

Methemoglobinemia (>1.5 g/dL)

Sulfhemoglobinemia (>0.5 g/dL)

Carboxyhemoglobin (produces cherry red discoloration)

b. Peripheral cyanosis

Low cardiac output

Local vasoconstriction (cold, frostbite, and Raynaud’s phenomenon)

Arterial obstruction

Venous obstruction

Hyperviscosity conditions (multiple myeloma and polycythemia)

Cryoglobulinemia

c. Mixed cyanosis

Left ventricular failure (has both central and peripheral cyanosis)

2. Pseudocyanosis

Metals:

Gold

Silver

Mercury

Arsenic.

Drugs:

Minocycline

Chloroquine

Amiodarone.

Atypical presentation of cyanosis

Description Example

Differential cyanosis Cyanosis is seen in only lower limbs PDA with eisenmengerization

Reverse differential cyanosis Cyanosis is seen in only upper limbs PDA with eisenmengerization and

transposition of great arteries

Three by four cyanosis In addition to lower limbs, the left upper limb may

also be cyanosed

When the patent ductus opens proximal

to the origin of left subclavian artery

Intermittent cyanosis Seen in Ebstein’s anomaly

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Cyclical cyanosis Bilateral choanal atresia

Orthocyanosis Development of cyanosis only in upright position

due to hypoxia occurring in erect posture

Seen in pulmonary arteriovenous malformation

Cyanosis absent despite of

sufficient reduced hemoglobin

In severe anemia, carbon monoxide

poisoning

Differences between Central and Peripheral Cyanosis

Central cyanosis Peripheral cyanosis

Due to inadequate oxygenation of systemic circulation Due to sluggish peripheral circulation

It is a hypoxic hypoxia It is a stagnant hypoxia

Site of examination: Tongue (Fig. 2C.12)

Oral mucosa (Fig. 2C.13)

Site of examination:

Tip of nose

Ear lobule

Outer lips

Finger tips

Nail bed

Extremities

Extremities are warm Extremities are cold

Do not improve on rewarming Improves on rewarming

PaO2 <85% PaO2 >85

Improves on oxygenation Does not improve with oxygenation

Dyspnea and high volume pulse seen Usually absent

Exercise may worsen Exercise may improve

May be associated with clubbing and polycythemia

Note: Cyanosis is best appreciated in areas of the body, where the overlying epidermis is thin and the

blood vessel supply abundant, such as the lips, malar prominences (nose and cheeks), ears, and oral

mucous membranes (buccal and sublingual); it is better appreciated in fluorescent lighting.

Fig. 2C.12: Demonstration of central cyanosis. (In this patient mucosa is pink and lingual veins can be

clearly demarcated, which is normal).

Fig. 2C.13: Bluish discoloration of tongue and oral mucosa suggestive of central cyanosis.

Hyperoxia Test (Cardiac vs Pulmonary Cyanosis)

After giving 100% oxygen for 10 minutes, a repeat arterial blood gas (ABG) is done and if PaO2

is <150

mm Hg then the cause is cardiac and if the PaO2

improves to >200 mm Hg, the cause is respiratory.

Iron Replete Cyanosis Versus Iron Deplete Cyanosis

Iron replete cyanosis Iron deplete cyanosis

It is compensated erythrocytosis which establishes

equilibrium with hematocrit

It is decompensated erythrocytosis which fails to establish equilibrium

with unstable, rising hematocrit

Iron replete cells are deformable Iron deplete cells are less deformable

Hyperviscosity symptoms are rare Hyperviscosity symptoms are frequent

Theories of Cyanosis

Admixture cyanosis Secondary to shunts

Tardive cyanosis Due to reversal of shunt (eisenmengerization)

Hypoxic cyanosis Due to type 1 respiratory failure

Replacement cyanosis Due to abnormal hemoglobins

Distributive cyanosis Venous pooling of blood

CLUBBING (HIPPOCRATES FINGERS)

Definition

Selective bulbous enlargement of distal segment of digits with subsequent loss of normal angle between

the nail and nail bed.

Theories of Clubbing

PDGF (role of

platelet)

The megakaryocytes preferably lodge in the tips of the digits and locally release platelet derived growth

factor (PDGF) and vascular endothelial growth factor (VEGF). These growth factors along with other mediators increase endothelial permeability and activate and cause proliferation of connective tissue

cells (e.g. fibroblasts)

Neurogenic Persistent vagal stimulation causes vasodilation and clubbing (e.g. lung carcinoma)

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Hypoxic Causes opening of deep arteriovenous fistula in fingers (e.g. tetralogy of Fallot)

Ferritin

Prostaglandins

Bradykinin

Adenine

nucleotides

5-

hydroxytryptamine

Circulating vasodilators, which are usually inactivated as blood passes through the lungs, bypass the

inactivation process in the patients with right to left shunts

Grades of clubbing (Figs. 2C.14 to 2C.19)

Grade 1 Increased fluctuation of nail bed

Grade 2 Loss of Lovibond angle/onychonychial angle (normal is <180°)

Profile sign

Schamroth sign

Grade 3 Parrot beaking

Drumstick fingers (seen in severe cyanotic heart disease, bronchiectasis, and empyema)

Grade 4 Pain along the distal ends of long bone due to subperiosteal new bone formation

Condition seen generally seen with bronchogenic carcinoma

Grade 5 Glossy changes in nails and adjacent skin with longitudinal striations(as proposed by Lung India)

Causes of clubbing

Respiratory causes

Malignancies Bronchogenic carcinoma

Mesothelioma

Suppurative diseases Bronchiectasis

Lung abscess

Empyema

Interstitial lung disease (ILD)

Tuberculosis Seen in 30% cases as a sequelae to complications

Sarcoidosis Can be seen

Cardiac causes

Subacute bacterial endocarditis

Atrial myxoma

Cyanotic heart disease

Acyanotic heart disease with Eisenmengerization

Gastrointestinal causes

Inflammatory bowel disease

Ulcerative colitis

Crohn’s disease

Primary biliary cirrhosis

Hepatocellular carcinoma

Neurological causes

Syringomyelia

Median nerve injury

Hemiplegia

Miscellaneous

Pachydermoperiostosis (pan digital hereditary clubbing)

Touraine-Solente-Gole syndrome

Note: Chronic obstructive pulmonary disease (COPD) never causes clubbing.

Fig. 2C.14: Demonstration of grade 1 clubbing.

Fig. 2C.15: Demonstration of profile sign.

Fig. 2C.16: Demonstration of Schamroth’s sign.

Fig. 2C.17: Demonstration of grade 3 clubbing.

Fig. 2C.18: Demonstration of grade 4 clubbing.

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