LIVER DISORDERS

D. VHANDA 2021
Blood supply of liver

• Blood flow ~ 1500 mL/min

• ~ 25% of cardiac output (what the heart pumps)

• Dual blood supply

• Nature of blood flow

• Hepatic artery 1/3

• Venous blood (portal vein) from the intestine 2/3

• This dual blood supply serves three important functions.

• 1. The dual blood supply gives a safety cushion to the liver and keeps it alive even if one
supply is terminated because of some pathological state.
• 2. The venous blood carries several harmful substances, toxins and biological products
derived from food and gut bacteria present in the large intestine; the liver acts as a filter
that prevents the systemic circulation from exposure to these substances; when this filter
function of the liver is impaired, such as in patients with liver failure, these harmful
substances reach to the brain and the patient becomes unconscious.
• 3. Venous blood carries a lot of nutrients from the small intestine which if released
unchecked into the circulation will produce metabolic imbalance – the liver acts as a
temporary warehouse to store excessive nutrients before release in times of need eg
fasting
 Causes of liver injury
• The liver can be damaged by many insults.

• Major causes

– Infections, especially viruses

• Hepatitis viruses – A to E

– Non-infectious causes

• Alcohol

• Drugs (anti TB drugs such as INH, Rifampicin, anti

epileptics, paracetamol, contraceptives etc)

• Non-alcoholic fatty liver disease

 Response of the liver to injury

• Acute (short-term) injury (sudden and massive death of hepatocytes)

– Inflammation

– Swelling and mild enlargement

– Death of cells and impairment of liver function

• Chronic (long-term) injury (slow but long standing injury which leads to cell death and
healing)

– Chronic inflammation

– Fibrosis (scarring)
Effect of liver injury

• Two effects
• Impairment of liver function
• Impairment of blood circulation through the liver
 Liver function and diseases
• Several functions, including some of the following
Glucose metabolism
• During the feeding phase Blood sugar too high (hyperglycaemia)
• During fasting Blood sugar too low (hypoglycaemia)
Excretory function
• Bile pigments (bilirubin) Jaundice
• Bile salts Poor absorption of fats
• Other harmful substances Unconsciousness
Synthetic function
• Albumin Edema, (ascites)
• Coagulation factors Deranged coagulation, bleeding
 Liver main cell structure
1.Parenchymal cells 60%
2.Bile canaliculi 10% and others
3.Kupffer cells 30% (RE system)
LIVER AND BILIARY TRACT FUNCTIONS
1. Synthesis : CHO, Protein and Lipids
•2. Metabolism : “ “ “
3. Storage : CHO, Vitamins Fats
4. Detoxication : Chemical change of toxic substances by
conjugation & excretion
•5. Transport : eg. bile acids
•6. Excretion eg bilirubin 8
 Protein Synthesis

• Primary site of synthesis of proteins (except immunoglobulins)

• Impaired liver function will result in decreased synthesis of some of the proteins -
albumin.

• However, injury, inflammation or trauma, burns -there is increased synthesis of

certain proteins - acute phase proteins - C-reactive protein, haptoglobin, alpha-1-
antitrypsin.

• Infection - would cause an increase in total protein as a result of increase of

immunoglobulins.

• Amino acid synthesis and degradation takes place in hepatocytes

 Carbohydrate Metabolism
• Converts glucose to glycogen (glycogenesis) during excess carbohydrate intake and
converts glycogen to glucose (glycogenolysis) during times of high-energy demand or
lowered glucose concentration.

• Converts lactate produced as a result of excess muscle work back to glucose.

• Synthesises glucose from amino acids (gluconeogenesis)

 Lipid Metabolism

• Active centre for lipid anabolism and catabolism.

• It synthesises endogenous lipids (triglycerides, cholesterol and

phospholipids), lipoproteins necessary to transport these lipids to the
tissues.

• Lipogenesis takes place in hepatocytes

 Other synthesis or transformations

• Transamination (transfer of amino group i.e. conversion of a keto acid to an amino

acid with concomitant production of a new keto acid), production of ketone bodies
(acetoacetic acid and beta-hydroxybutyric acid) from acetyl CoA, conversion of some
amino acids to glucose and vice versa.
Storage functions

• Primary store for glycogen, vitamin A, D and B12, and Fe (also stored in the
bone marrow & spleen).

• Normally, storage of lipids in the liver is limited.

 Excretory functions

• Secretes bile into the bile canaliculi

• Bile contains, conjugated bilirubin, bile acid conjugates, cholesterol,

phospholipids, organic anions, soluble derivatives of steroid hormones and
drugs, electrolytes.
 Protective functions and Detoxification
Various foreign and dangerous materials are taken up by phagocytosis by the Kupffer
cells, which act as scavengers followed, by detoxification reactions.

Drugs & other toxic substances

• Most insoluble or relatively insoluble compounds including therapeutic drugs are

converted to either less toxic or water soluble and excreted in bile or urine. The
enzymes are located in the smooth endoplasmic reticulum.

• Two types of reaction: Phase I – oxidation or demethylation by the Cytochrome P450

system; phase II metabolism in which phase I metabolites are converted to water-
soluble compounds – e.g. glucuronide etc.
 Liver function and disease

• Impaired excretion of bilirubin results in jaundice.

• Impaired clearance of toxic wastes may lead to unconsciousness.

• Albumin is the main protein that maintains the oncotic pressure and maintains the body
vascular volume.

• If albumin is not synthesized then fluid will move out from the blood vessels to the third
spaces such as the peritoneal cavity and pleural cavities.

• It results in ascites and pleural effusion.

• Impaired synthesis of coagulation factors will lead to bleeding manifestations.

RANGE OF LIVER AND BILIARY TRACT DISEASES

1.Hepatocellular damage and necrosis (Toxic Infective Hepatitis)

2.Cirrhosis
3.Cholestasis or jaundiced or hyperbilirubinaemia
4.Biliary obstruction
5.Primary hepatocellular carcinoma
•Liver infections eg. Schistosomiasis, etc, and congenital defects

17
 Liver disease: Effect on blood circulation

• Obstruction of blood flow through the hepatic lobules leads to increased pressure in the
portal vein

• Portal hypertension = increased pressure in the portal vein

• Manifestations

– Development of collateral veins Abnormally enlarged veins (varices)

– Exudation of fluid into abdomen Ascites.

– Congestion of venous system Splenomegaly >pancytopenia

(thrombocytopaenia)
 Liver Function Tests (LFTS)
1. Battery of tests to test liver function
2. May give abnormal results with other systems, therefore cannot be used in isolation
3. Screening
4. Profiling
5. Prognosis
6. Monitoring progress
7. Evaluation of new therapy
8. a) Sensitivity : → detects disease + exclude without diseases
b) Specificity : → minimises false positives
c) Predictive value : positive result → disease
negative result → no disease
 Uses of LFT’S
• 1. Screening on apparently healthy individuals,

• 2. Profiling -routinely on patients

• 3. Diagnosis

• 4. Monitoring- general state of patient, particular disease, response to therapy,

complications

For LFT's to be useful there is need for knowledge on:

1. Significance of individual tests both when abnormal and when apparently normal

2. Pattern of abnormalities and how they change during the course of the disease
 LFT PANEL

1.Total protein
2.Albumin
3.Total bilirubin
4.Conjugated bilirubin
5.Cholesterol
6.Alanine aminotransferase (ALT)
7.Aspartate aminotransferase (AST)
8.Alkaline phosphatase (ALP)
9.Gamma glutamyl transferase (GGT)
10. 5` nucleotidase
11. Protein electrophoresis
12. Immunoglobulins
13. Urine bilirubin and urobilinogen
14. Coagulation studies
 Albumin
• -hepatic synthetic function - half-life 3 weeks

• Concentration depends on –
• 1. Nutritional status

• 2. Rate of degradation

• 3. Synthesis

• 4. Leakage into ascites and other extracellular compartments (e.g.GIT) .

• 5. State of hydration

• 6. Kidney function (nephrotic syndrome)

• Low level usually means - Chronic disease and/or liver dysfunction

• Normal level- Does not always imply normal 'liver', 80% of out-patient cirrhotics have
1.Plasma proteins eg. Albumin ↓in chronic liver disease
2.Globulins↑ in liver disease

• Increased IgA ­ = alcoholic hepatitis

• Increased IgG ­ = autoimmune chronic active hepatitis
• Increased IgM = 1° biliary cirrhosis
 Bilirubin and Urobilinogen
• Total Bilirubin in blood

• Conjugated and unconjugated bilirubin in blood

• Measurement of conjugated and unconjugated bilirubin useful neonatal

jaundice

• Neonatal jaundice – 1. Kernicterus if unconjugated ­ 300 mmol/L in full-

term baby. 2. Monitoring -physiological jaundice. All others - pathological
• Bilirubin in urine
• Always pathological if detected.
• Will be detected even when no apparent jaundice and total bilirubin still 'normal'.
• Only conjugated bilirubin can be detected in urine

• Urobilinogen in urine -
• ­ Haemolysis
• Biliary obstruction, Diarrhoea, Antibiotics in gut
 Enzymes

• a). Enzymes – mainly for diagnosis of hepatocellular (intracellular) damage

• AST, ALT, (AST/ALT ratio)

• b). Enzymes – mainly for diagnosing biliary obstruction Alkaline Phosphatase (ALP)

• Alkaline phosphatases are a group of enzymes that splits a terminal phosphate group
from an organic phosphate ester in alkaline solution

• Widely distributed in the body (liver, bone, placenta, kidney and intestines)
 ALP

• Adults ~ 50% liver, 50% bone, Growing children ­bone

 -Usually 'total' activity measured - ­Children– Bone, Pregnancy- placenta, bone
disease – bone, biliary cholestasis (intra or extrahepatic), space - occupying lesions in
liver , liver - biliary
or hepatocellular, liver regeneration, 'Regan' isoenzyme - a placenta- like foetal form
• Hepatocellular necrosis - Increased hepatocellular ALP
• Biliary obstruction - Increased biliary ALP
• Cirrhosis - Increased biliary, hepatocellular ALP
 Gamma Glutamyl transferase (GGT)
• Catalyses - transfer of a glutamyl group from one peptide to another.

• Present in-liver, kidney, pancreas, prostate, most tissues. It is higher in men than
women

• Enzyme induction especially in chronic alcohol abusers, subjects on warfarin and

antiepileptics and in cholestasis.

• Sensitive but not specific (because of widespread distribution) and also can be raised
due to severe damage of any tissue, MI, heart failure etc.
• For practical purposes used only to check if a raised ALP is of liver origin (when
isoenzymes are not available) and for screening for alcohol abuse and enzyme induction.

• 5' nucleotidase - used occasionally in conjunction with gGT to confirm that raised ALP is
of liver origin

• Lactate Dehydrogenase (LD or LDH) has widespread tissue distribution including liver,
red blood cells, skeletal and cardiac muscle.

• Tissue-specific isoenzymes can be separated by electrophoresis.

• The LD5 isoenzyme is found in liver and skeletal muscle only.

 LFT Patterns

 ­Bilirubin with normal other LFT= haemolysis, Gilbert's syndrome

 ­Bilirubin + one other index = hepatobiliary disease

Relationship of ALP and AST or ALT

• Increased ALP Normal to increased AST/ALT = cholestasis

• Normal to increased ALP Increased AST/ALT= hepatocellular disease

• 1° biliary cirrhosis, acute alcoholic hepatitis, malignancy or any space occupying

lesion in liver - often ALP ­alone ± ­bilirubin
AST

• Found in the liver, heart, skeletal muscle, kidney, red blood cells, pancreas

• Found in cytosol and mitochondria of liver

• Raised artefactual –haemolysis, Neonatal period-up to 1.5X upper adult level

• Cirrhosis, cholestasis, 1°, 2° malignancy, skeletal muscle disease, surgery,

haemolysis, sepsis -- up to 10X upper adult level

• Shock, hypoxia, myocardial infarction, acute/chronic hepatitis, toxic (but not

alcoholic) hepatitis, sepsis, - 10-100X upper adult level
 ALT
• Found in the liver, skeletal muscle, kidney, heart - cytoplasm

• Raised-Cirrhosis, hypoxia, congestion, Cholestasis, Muscle disease, Shock,

Sepsis, Acute/chronic viral hepatitis, Toxic hepatitis

• is the most sensitive and specific marker of hepatocellular damage.

• It is preferred over AST because of its specificity to the liver

• AST/ALT ratio
• if ­ 2- alcoholic cirrhosis or hepatitis, reduced amount of liver tissue, severe
necrosis
• If 1- extrahepatic obstruction or viral hepatitis
 Range of liver and biliary tract disease

• 1. Cholestasis

• Ø Cholestasis is stagnation of bile flow

• Ø In cholestasis there is regurgitation of conjugated bilirubin into the general circulation

• A. May be intrahepatic-bile secretion from the hepatocytes into the canaliculi is impaired

• Ø Causes –Viral hepatitis infection, toxic hepatitis due to drugs, inflammation of the

biliary tract, primary biliary cirrhosis

• B) Extrahepatic-due to obstruction to the flow of preformed bile through the biliary
tract by stones, inflammation or pressure by malignant tissue

• Ø It is essential to distinguish between extra and intrahepatic causes of cholestasis

• Ø Diagnosis increased total bilirubin, increased conjugated bilirubin, increased ALP,

increased GT, increased bile acids and cholesterol but plasma ALT and AST
activities usually moderately raised
• Biochemical tests alone can not distinguish between intra and extra hepatic
cholestasis ? Ultrasound scanning, isotopic imaging, histology etc

• Presentation with severe jaundice and itching due to deposition of retained bile salts
in the skin

• Rarely presentation with bleeding due to vitamin K malabsorption, with consequent

prothrombin deficiency

• Urine dark and pale stools suggests biliary retention of conjugated bilirubin
Hepatocellular damage

• Acute hepatitis

• Hepatitis characterized by necrosis and inflammation of hepatocytes-----

functional ability decrease and abnormal LFTS

• Viral infection mononucleosis, rubella, CMV, Hep A, B, C, D,E

• Acute alcoholic hepatitis –occurs in excessive alcohol drinkers

• Drugs and toxins directly or due to hypersensitive reactions

• Drugs history is essential

• Chronic Hepatitis

• Chronic persistent hepatitis

• Chronic active hepatitis-active and continuous hepatocellular destruction, may progress

to cirrhosis

• Causes viral (HbsAg), autoimmune process, idiopathic

• Hepatitis is characterized by necrosis and inflammation of the hepatocyte, which

results in a decrease in functional ability and abnormal LFT results
• Jaundice is apparent later in the disease

• Serial determination of ALT/AST levels preferred in acute hepatitis.

• AST/ALT return to normal 2-3months after clinical recovery.

• Abnormal AST/ALT values that persist for 6 months indicate chronic hepatitis
 Cirrhosis (yellow orange conditions of liver)
• Terminal stages of inflammation and metabolic disease involving the liver

• Causes chronic excessive alcohol intake, autoimmune disease, persistence of Hep

B virus, Hepatitis C, Schistosomiasis, IEOM eg Wilson’s disease,
haematochromatosis and alpha 1 antitrypsin deficiency

• Diagnosis albumin normal to decreased, Bilirubin normal to increased, AST/ALT

normal to increased, ALP normal to increased, PT normal to increased
Primary Hepatocellular carcinoma (HCC)

• Associated with hepatitis B and C viruses, iron overload and aflatoxins

• Secondary due to tumour metastasis

• Diagnosis alpha fetoprotein increased in 70-80% of cases, LFTS are of

little value in diagnosis, ALP increased, liver biopsy is diagnostic
 Fulminant hepatic failure

• Clinical syndrome develops when there is massive liver cell necrosis

• Rare condition

• Associated with viral hepatitis and paracetamol poisoning

• Metabolic disturbance is profound and prognosis is poor

• Renal failure may accompany the condition

• Diagnosis severe hyponatraemia, hypocalcaemia, hypoglycaemia, hydrogen ion

homeostasis is disturbed, decreased urea due to decreased synthesis, PT is
prolonged and bleeding may be common
 Iron overload

• Haemachromatosis

• African iron overload

• Iron deposition in the liver may cause cirrhosis

• Diagnosis Increased iron (not sensitive non specific), decreased TIBC, increased
ferritin (shows correlation with iron stores), increased transferrin saturation
 Others

• Alpha 1 antitrypsin deficiency associated with neonatal hepatitis

• Galactosaemia if untreated may cause cirrhosis

• Wilson’s disease due to excessive accumulation of copper may cause hepatitis and
cirrhosis in young adults

• Reyes syndrome rare cause of acute fatty infiltration of the liver in children
 Primary biliary cirrhosis (PBC)
• Progressive autoimmune based disorder

• Aetiology unknown

• Predominantly affects middle aged women

• There is destruction of bile ducts, inflammation and scarring

• Diagnosis antimitochondrial abs (90% cases), increased ALP, increased IgM

• Definitive diagnosis is based on liver biopsy finding

 Coagulation studies
• Clotting factors have short half-lives, e.g. factor VII t½ = 4h

• Prothrombin time (INR) and partial thromboplastin time (PTT) may be prolonged in
liver disease due to decreased synthesis of clotting factors or secondary vitamin K
deficiency resulting from fat malabsorption.
 Formation of Bilirubin

• Haemoglobin is broken down to globin and haem.

• Globin (a protein) is broken down to its constituent amino acids.

• Haem (a 4 ring structure containing Fe at its centre) is broken down (via biliverdin) to
carbon monoxide, iron and bilirubin.

• Biliverdin gives the green colour sometimes seen in a resolving bruise.

• The bilirubin at this stage is termed unconjugated bilirubin because it has not yet been
processed by conjugation in the liver
 Disorders of Bilirubin metabolism

• Jaundice (Tbil greater than 50mol/L)

• Is a condition characterized by a yellow discoloration of the skin, sclera and mucous

membranes

• Conjugated bilirubin causes more jaundice than unconjugated bilirubin because of

easier absorption into tissues and higher water solubility

• Liver has a large reserve capacity - jaundice only appears with severe impairment of
liver function.
 Classification of jaundice
• Anatomic-pre, -hepatic, post hepatic

• Pre and post hepatic jaundice – liver function not impaired, liver functioning maximum
capacity in compensatory effort to alleviate problems caused by other factors
 Pre hepatic jaundice

• Caused by an increased production of Bilirubin

• Increased destruction of rbc (haemolytic disorders)-malaria, bacterial toxins causing

haemolysis, blood group incompatibility, autoimmune haemolytic anaemias, rbc
enzyme/membrane defects

• Ineffective erythropoiesis

• Increased turnover of non Hb heme compounds

• Diagnosis in serum, Total bilirubin normal to increased, conjugated bilirubin normal to

increased, Unconjugated bilirubin increased, albumin normal, AST/ALT normal

• Urine urobilinogen increased and bilirubin normal (Negative)

• Haematological tests (Coombs test, RBC morphology, abnormal hb, reticulocyte count)
 Hepatic (Hepatocellular) jaundice
• Two types

i) Retention jaundice

• Defect in the transport of bilirubin into the hepatocyte

• Causes are physiologic jaundice of the newborn, Gilbert’s syndrome, Criggler-Najjar

syndrome

• Unconjugated bilirubin is predominant type found in plasma

• ii) Regurgitation jaundice

• Hepatic cell is damaged or defective or the excretion of products from the hepatocyte
is impaired

• Diagnosis is by conjugated bilirubin which is the predominant type found in plasma

• Causes are Dubin Johnson, Rotor syndrome, cirrhosis, viral hepatitis, drug induced
liver disease, hepatocellular carcinoma, toxic liver injury and cholestasis jaundice of
pregnancy

• In serum Total bilirubin is increased, conjugated bilirubin is increased, unconjugated

bilirubin is increased, AST/ALT increased

• In urine bilirubin and urobilinogen are increased

 Congenital hyperbilirubinaemias

• Gilbert’s syndrome
• Autosomal (dorminant) inheritance

• Lesion-UDP Glucoronyl transferase has reduced activity 20-50% also abnormal

Bilirubin uptake

• Diagnosis is by slight increase in unconjugated bilirubin

• 2. Crigler Najjar Syndrome

• 2 types type 1 and 11.

• Type 1 more severe

• Lesion –UDP Glucoronyl transferase deficiency. Autosomal recessive inheritance

• Type 1 Severe in neonates. Severe mutation of UDPGT I gene leading to absent

UDPGT I activity. Kernicterus and early death (1year survival). Rare condition.
Diagnosis Bilirubin increased 340-850mol/L. Urine urobilinogen and bilirubin negative.

• Type 11- Milder mutation of UDPGT I gene leading to reduced UDPGT I activity.
UDPGlucuronyl transferase less than 10% activity. Diagnosis by increased Bilirubin (but
less than 340mol/L). Kernicterus is rare. Jaundice is only symptom.
• 3. Dubin Johnson

• Defect is impaired transfer of conjugated bilirubin to biliary canaliculi.

• Autosomal recessive inheritance.

• Diagnosis -standard LFTs are normal. Benign increase in Bilirubin (34-170mol/L

60% conjugated bilirubin).

• Urine Bilirubin increased (dark urine)

• 4.Rotor syndrome

• Similar to Dubin Johnson but no hepatic pigmentation

 Post hepatic jaundice (cholestasis)

• Is caused by a blockage of the flow of bile from the liver

• Liver hepatocytes are not faulty

• Causes blockage by bile duct stones, neoplasms of the bile ducts, pancreas, bile duct
stricture or stenosis

• Diagnosis serum conjugated bilirubin, unconjugated bilirubin (prolonged cholestasis

liver may be damaged), ALP are increased.

• ALT/AST normal to increased.

• Urine Bilirubin increased, urobilin decreased or negative. Stool is chalky white.

 Neonatal jaundice

• Newborn expected to have a much higher bilirubin concentration than adult due to
significant haemolysis occurring during birth as well as infant’s immature liver

• Bilirubin peaks 2 to 3 days postpartum, followed by a rapid fall to normal infant

concentration

• If elevated bilirubin persist beyond 2 weeks or continue to increase above

250mol/L---- liver dysfunction must be investigated eg Rhesus incompatability,
neonatal hepatitis, inherited liver dysfunction
 Neonatal Jaundice
• In utero, bilirubin is transported across the placenta, conjugated and excreted by the
mother's liver.
• After birth the neonate must excrete the bilirubin.
• Factors contributing to neonatal jaundice:
• Shorter RBC lifespan.
• Immature liver, especially in premature neonates.
• Takes 2-4 weeks to develop fully.
 Unconjugated Hyperbilirubinaemia
• :TYPES
• Physiological jaundice
• Jaundice develops on days 3-5 (never on day 1).
• Levels of bilirubin may reach 150 μmol/l, all unconjugated.
• Usually phototherapy is all the treatment that is required.
• Blood group incompatibility ("haemolytic disease of the newborn”) Jaundice
develops on day 1.
• Rhesus or ABO systems commonly responsible, others rarely.

• A few foetal RBCs cross into maternal circulation, mother makes antibodies if blood
groups are incompatible.

• These IgGs then pass into foetal circulation, causing haemolysis of foetal RBCs.

• Excessive bilirubin production is not a problem for the foetus, since it crosses
placenta and is conjugated, excreted by mother's liver.

• However, bilirubin starts rising rapidly after birth. Severe haemolysis in utero causes
foetal anaemia and heart failure ("hydrops foetalis").

• Inherited haemolytic disorders.

 COMPLICATION

• Risk of kernicterus when unconjugated bilirubin > 200 μmol/l.

• Free unconjugated bilirubin is neurotoxic.

• At high concentrations it deposits in cell membranes (esp. basal ganglia)

causing kernicterus.

• Risk is increased by other factors:

• Level of unconjugated bilirubin.

• Low albumin.

• Drugs (displace bilirubin from albumin).

• Acidosis (promotes dissociation of bilirubin from albumin).

• Heparin administration (causes liberation of free fatty acids which displace bilirubin
from albumin).

• Hypoxia, hypoglycaemia, hypothermia, sepsis (increase bilirubin transport into the

brain).

Features: - Lethargy, hypotonia (low muscle tone/reduced muscle stamina and

endurance), poor feeding, spasticity (involuntary muscle contractions that are not
coordinated with other muscles) and death.
 Conjugated Hyperbilirubinaemia:
• TYPES

• Neonatal hepatitis (inflammation of the liver causing intrahepatic cholestasis)

• Many infective agents can cause hepatitis in neonates (e.g. rubella, CMV, herpes
simplex, toxoplasmosis).

• Biliary atresia

• Cause of biliary atresia is unclear: may be toxic degeneration of bile duct rather than a
congenital malformation. It’s a rare condition associated with blocked/absent common
bile duct between the liver and the small intestines

• Metabolic disorders/genetic disorders

 Coagulation studies
• Clotting factors have short half-lives, e.g. factor VII t½ = 4h

• Prothrombin time (INR) and partial thromboplastin time (PTT) may be prolonged in
liver disease due to decreased synthesis of clotting factors or secondary vitamin K
deficiency resulting from fat malabsorption.